DRUG DISPOSITION

Clin. Pharmacokinet. 21 (3): 178-194. 1991 0312-5963/91 /0009-0178/$08.50/0 © Adis International Limited. All rights reserved. CPK1052

Clinical Pharmacokinetics of Famotidine Hirotoshi Echizen and Takashi Ishizaki Division of Clinical Pharmacology. Clinical Research Institute, National Medical Center, Tokyo, Japan

Contents 178 179 180 180 184

184 184 185 185

186 187 187 187 188 188 189

190 190 190

191

Summary

Summary I. Analytical Methods 2. Pharmacokinetic Characteristics of Famotidine 2.1 Pharmacokinetics After Single Intravenous Doses 2.2 Plasma Protein Binding 2.3 Pharmacokinetics After Single Oral Doses 2.4 Pharmacokinetics During Multiple-Dose Administration 3. Effect of Age and Disease State on Pharmacokinetics 3. 1 Age 3.2 Disease State 4. Haemodialysis and Haemofiltration 4.1 Haemodialysis 4.2 Haemofiltration 5. Dose- or Concentration-Response Relationship 5. 1 Dose- or Concentration-Antisecretory Response Relationship 5.2 Therapeutic Implications of Concentration-Response Data 6. Drug Interaction Potential 6.1 Hepatic Metabolism 6.2 Renal Excretion 7. Conclusions and Therapeutic Implications

Famotidine is a potent histamine H2-receptor antagonist widely used in the treatment and prevention of peptic ulcer disease. After intravenous administration the plasma famotidine concentration-time profile exhibits a biexponential decay, with a distribution half-life of about 0. 18 to O.5h and an elimination half-life of about 2 to 4h. The volume of distribution of the drug at steady-state ranges from 1.0 to 1.3 L/kg; plasma protein binding is low (15 to 22%). Famotidine is 70% eliminated unchanged into urine after intravenous administration. The total body and renal clearances of famotidine correlate significantly with creatinine clearance. Because its renal clearance (15 L/h) far exceeds the glomerular filtration rate, famotidine is considered to be eliminated not only via glomerular filtration but also via renal tubular secretion. Since its clearance is reduced in patients with renal insufficiency and in elderly patients, the maintenance dosage should be reduced in these patient groups. Removal of famotidine by any of the currently employed blood purification procedures (haemodialysis, peritoneal dialysis and haemofiltration) does not occur to a clinically significant degree. Liver cirrhosis does not appear to affect the disposition of famotidine unless severe renal insufficiency coexists. After oral administration, peak plasma

Pharmacokinetics of Famotidine

179

concentrations are attained within 2 to 4h; the oral bioavailability ranges from 40 to 50%, due mainly to incomplete absorption. The oral absorption of the drug is dose-independent within a range of 5 to 40mg. There are 3 formulations available (tablet, capsule and suspension), which appear to be bioequivalent. Coadministration of potent antacids reduces the oral absorption of famotidine by 20 to 30%. On a weight-to-weight basis, the anti secretory effect of famotidine is about 20 and 7.5 times more potent than those of cimetidine and ranitidine, respectively. Plasma famotidine concentrations correlate with its antisecretory effect: values of about 13 and 20 JLgfL produce a 50% reduction in the gastrin-stimulated gastric acid secretion and a fasting intragastric pH of >4, respectively. Available data suggest that famotidine interacts neither with the hepatic oxidative drug metabolism nor with the tubular secretion of other commonly used therapeutic agents. However, further studies are required to evaluate a full spectrum of its drug interaction potential.

Inasmuch as gastric acid may play an important role in the development of gastroduodenal mucosallesions (e.g. ulcer and erosion) [Baron 1982], the inhibition of gastric acid secretion by a histamine H2-receptor antagonist has been considered to be a cornerstone in the treatment and prevention of peptic ulcer disease and other allied clinical conditions (Piper 1983; Teres et al. 1980). Famotidine is a relatively new H2-receptor antagonist which is rapidly gaining wide clinical acceptance because of its potent antisecretory effect and relatively low drug interaction potential (CampoliRichards & Clissold 1986; Langtry et al. 1989). It is structurally related to 2 earlier H2-receptor antagonists, cimetidine and ranitidine, but differs principally in having a thiazole nucleus rather than an imidazole nucleus (cimetidine) or a furan nucleus (ranitidine) [fig. 1]. Differences in the chemical structures of the H2-receptor antagonists may be associated with differences in their antisecretory potency, pharmacokinetics and drug interaction potential. On a weight-to-weight basis, famotidine is about 20 and 7.5 times more potent than cimetidine and ranitidine, respectively, in inhibiting basal and pentagastrin-stimulated gastric acid secretion in humans (Dammann et al. 1983; McCallum et al. 1985; Smith et al. 1985). Previous therapeutic trials (see the reviews by CampoliRichards & Clissold 1986; Langtry et al. 1989) have demonstrated that famotidine has a therapeutic efficacy comparable with the earlier H2-receptor antagonists in the treatment of gastric and duodenal

ulcer, when pharmacologically equivalent doses were compared.

1. Analytical Methods Famotidine is a weak base (pKa 6.7) and has a fairly high water solubility or hydrophilicity due to polar substituents in the side-chains. Its solubility in N,N-dimethylformamide, glacial acetic acid, methanol and water is 80, 50, 0.3 and 0.1 % w/v at 20°C, respectively, whereas in less polar organic solvents (e.g. alcohol, ethyl acetate and chloro-

Famotidine

Fig. 1. Structural formulae of farnotidine, ranitidine and cirnetidine.

180

form) the figure is <0.01% w/v (Vincek et al. 1985). Thus, the extraction of famotidine into waterimmiscible organic solvents has proved ineffective (Vincek et al. 1985). On the other hand, it was extracted effectively from biological fluids (e.g. plasma and urine) using a solid-phase column packed with a hydrophilic silica (e.g. 'Bond-Elut' silica) with or without additional purification with a watermiscible organic solvent (i.e. ethylacetate) [Carlucci et al. 1988; Kroemer & Klotz 1987; Rahman & Hoffman 1988; Vincek et al. 1985]. Famotidine was separated by reversed-phase high performance liquid chromatography (HPLC) using either a Cs or a cyano (CN) column and was detected by UV absorption (Carlucci et al. 1988; Kroemer & Klotz 1987; Rahman & Hoffman 1988; Vincek et al. 1985). The detection limits with the HPLC-UV detection methods ranged from 5 to 10 J.l.gjL in plasma and 10 to 500 J.l.g/L in urine. Kawai et al. (1984) have developed a novel fluorescent derivatisation method for famotidine assay in plasma and urine, using phenanthrenequinone as a fluorescent chromophore. However, because they published the assay method in a domestic (Japanese) journal and only its brief summary was available in English, this efficient analytical technique does not appear to have had a wide acceptance. Vincek et al. (1985) revealed that famotidine was somewhat unstable in urine at room temperature (22 to 2YC): there was a 10 to 15% loss in urinary drug concentrations over 4h. Thus, biological samples for famotidine assay should be frozen immediately after collection and stored at -15°C or lower until analysed.

2. Pharmacokinetic Characteristics of Famotidine 2.1 Pharmacokinetics After Single Intravenous Doses Following intravenous administration of famotidine, the plasma drug concentration-time profile exhibits a biexponential decay with a distribution half-life (tl/",) of 0.18 to 0.5h and an elimination half-life (tlhff) of 2.59 to 4h in healthy adult volunteers (Kroemer & Klotz 1987; Takabatake et al. 1985). Table I summarises the mean

Clin. Pharmacokinet. 21 (3) 1991

pharmacokinetic parameters of intravenous famotidine obtained from healthy adult volunteers and from adult and paediatric patients with normal renal function. 2.1.1 Distribution The apparent volume of distribution at steadystate (Vss) and during the terminal log-linear phase (Vz) of famotidine obtained from healthy adult volunteers range from 0.94 to 1.33 L/kg (Echizen et al. 1988; Kromer & Klotz 1987; Lin et al. 1988; Takabatake et al. 1985; Yeh et al. 1987). These values are largely comparable with those of cimetidine and ranitidine (Brogden et al. 1982; Somogyi & Gugler 1983). The volume of distribution (Vd) values obtained from healthy subjects do not appear to differ significantly from those observed in patients with renal failure or liver cirrhosis (see sections 3.2.1 and 3.2.2). Although no systematic studies have been made, analysis of the cumulative data in the literature suggests that the Vd of famotidine may decrease with aging (see section 3.1 and fig. 2). The mean apparent volume of distribution for the central compartment (V d is reported to be 0.34 L/kg in patients with normal renal function (Takabatake et al. 1985); the relatively small Vss and Vc for famotidine may be associated with its rather high water solubility. Only limited information is available on the tissue distribution of famotidine in humans. Using an ex vivo placenta perfusion model, Dicke et al. (1988) have shown that famotidine is transferred through the human placenta at a rate similar to that of other H2-receptor antagonists (i.e. cimetidine, ranitidine and nizatidine). However, at present no data are available as to whether a clinically significant amount of famotidine would be transferred into the human fetus. Cimetidine and ranitidine are both excreted into human breast milk at milk/plasma (M/P) ratios ranging from 3 to 12 and from about 1 to 4, respectively (Riley et al. 1982; Somogyi & Gugler 1979). Famotidine is also excreted into human breast milk at a mean M/P ratio of I. 78 at 6h after a single oral dose of 40mg in 8 puerperal women (Courtney et al. 1988). The mean daily yield of milk

181

Pharmacokinetics of Famotidine

Table I. Mean pharmacokinetic parameters of intravenously administered famotidine in healthy adult subjects, and in adult and paediatric patients with normal renal function

Reference

Takabatake et al. (1985) Yeh et al. (1987) Morgan & Stambuk (1986) Kraemer & Klotz (1987) Lin et al. (1988) Echizen et al. (1988) Koaus et al. (1990)

Mean age (y)

No. of subjects

Dose (mg)

Vc (L/kg)

Vss (L/kg)

tv.p (h)

CL (L/h)

CLR (L/h)

CLNR (L/h)

0.34

1.14

2.6

24.7

18.2

6.54

72.3 [0-24)8

29.3 27.0 24.9 18.5

13.3

5.30

71.5 [0-24)

0.127 0.040

66.8 [0-72) 78.7 [0-72)

45

7b

20

NA NA 30

8c 8c 5c

10 20 20

1.28

2.4 2.8 3.2

35

3c

20

1.13

4.0

26 69 24 48 5

16c 8c 6c

20 20 0.1 8 0.1 8 0.38

1.33 0.94 1.30' 1.20' 1.41

2.9 4.1 2.2 2.8 3.3

89 10h

0.394ct 0.192ct O.43d 0.38d

0.266 0.155

0.3oct

Ae (%) [time (h))8

53.3 [0-12)

a Urine collection period. b Patients with normal renal function. c Healthy volunteers. d L/h/kg. e mg/kg. f Vz . 9 Patients with upper gastrointestinal bleeding. h Paediatric patients who underwent cardiac surgery. Abbreviations: Vc = apparent volume of central compartment; Vss = apparent volume of distribution at steady-state; Vz ... apparent volume of distribution during the terminal phase; tl'2,8 terminal plasma half-life; CL total body clearance; CLR renal clearance; CLNR nonrenal clearance; Ae amount of unchanged drug excreted in urine (% dose); NA not available.

=

=

=

ranges from 600 to 800 ml/day in Caucasian women (Wilson et al. 1980); thus, assuming that the peak concentration (Cmax) offamotidine attainable after an oral dose of 40mg is about 100 JLg/L, the maximum amount of the drug which could be ingested by a nursing infant less than 1 year old would be calculated to be about 0.14 mg/day or 0.015 to 0.04 mg/kgjday (i.e. equivalent to about 1 to 3 mg/day in a 70kg adult subject). If this assumptive estimate is correct, the excretion of famotidine into human breast milk would be clinically insignificant. H2-Receptor antagonists, particularly cimetidine, are claimed to produce neurological side effects (e.g. mental confusion) [Brogden et al. 1982; Schentag et al. 1979; Somogyi & Gugler 1983]. Be-

=

=

=

cause the development of neurotoxicity from these drugs has been suggested to be associated with high drug concentrations in plasma and cerebrospinal fluid (CSF) [Schentag et al. 1979], the distribution offamotidine into the central nervous system (CNS) is of clinical interest. Famotidine distributes into CSF at a mean CSF/plasma concentration ratio of 0.12 at 4h after oral administration in patients with intact blood-brain barrier (Kagevi et al. 1987). The ratio is less than that of cimetidine (0.24) [Schentag et al. 1979] but may be somewhat higher than that of ranitidine (0.06 at 4h postdose) [Kagevi & Wahlby, 1985]. We have recently encountered 2 patients who developed mental confusion during famotidine

Clin. Pharmacokinet. 21 (3) 1991

182

therapy. Both patients had severe renal insufficiency and were given famotidine to prevent stressinduced ulceration after a neurosurgical operation for the treatment of subdural haematoma. Their CSF/plasma ratios of famotidine were unexpect-

y = 1.47 - 0.0073x

1.5

r = -0.943 P < 0.001

1.25

1.0

0.75

a

0

20

40

= 34.8 - 0.279x r = -0.764

y

35

P < 0.05

30

• •

25

~ ...J

20

U

80

60

•

15

•

10

o b

20

40

60

80

Age (y>

Fig.2. Relationships between age and famotidine (a> volume of distribution (Vd) and (b) total body clearance (eL) normalised to 70kg bodyweight. Data are mean values from the studies in table I, with the exception that clearance values in paediatric patients were omitted owing to the difficulty in normalising them to a 70kg adult value.

edly higher (i.e. 0.38 and 0.63, unpublished data) than the ranging values (i.e. 0.06 to 0.17) observed in patients with a normal blood-brain barrier (Kagevi et al. 1987). The neurological symptoms of both patients disappeared promptly after withdrawal of famotidine therapy. These data suggest that the distribution or penetration of famotidine and possibly other H2-receptor antagonists into the CNS may be enhanced in patients with a bloodbrain barrier functionally disrupted by trauma, neurological operation or inflammation. 2.1.2 Metabolism At present, famotidine S-oxide is the only known metabolite of the drug in humans (unpublished data on file, Yamanouchi Pharmaceutical Co., Tokyo, Japan). After intravenous administration of famotidine, about 2 to 8% of the dose was recovered in urine as famotidine S-oxide in humans (Kroemer & Klotz 1987; unpublished data on file, Yamanouchi Pharmaceutical Co.). Previous studies (Lin et al. 1988; Takabatake et al. 1985; Yeh et al. 1987) have demonstrated that the nonrenal clearance (CLNR) offamotidine consisted of only 21 to 33% of the total plasma clearance (CL) [table I]. Therefore, the hepatic metabolism of famotidine would make only a minor contribution to the overall elimination of the drug. The biological activity of famotidine S-oxide, if any, is currently unknown. 2.1.3 Elimination Famotidine is predominantly excreted unchanged into the urine. Following an intravenous infusion, the urinary recovery of the unchanged form ranged from 67 to 79% over 72h (Lin et al. 1988). In addition, because the renal clearance (CLR) offamotidine obtained from healthy volunteers (e.g. about 300 mlfmin) far exceeds the normal value for glomerular filtration rate (100 to 120 ml/min) [table I], this H2-receptor antagonist is considered to be eliminated by the kidneys via both glomerular filtration and renal tubular secretion. Indeed, the renal elimination of famotidine is reduced in patients with renal insufficiency, in pro-

Pharmacokinetics of Famotidine

1.S 1.4

~ 1.2

;;r

•

:g 1.0

•

•

•

>

0.8

183

•

,

•

20

y = -1.0S + O.17Sx

O.S OL-.---2.... 0 - - - 4.... 0 - - - S.....0---..",80

r

15

:2 30 25

•

y

= 19.2 -

d:II:

0.24Sx

10

...J

U

r = -0.8S P < 0.01

20

•

= 0.89

P < 0.01

5 O~~-~----L---~-----

o

10 5

8

O~--~----'----~-~~ 20 40 SO 80 o

7

•

y = 0.972 + 0.233x 20

r = 0.8S

15

d

10

5

II:

4

d

p
~

;;r

SO

y = 2.43 + 0.039x

••

3 2 1L-._ _

o

~

___

~

~

__

~

80

•

r = 0.S5 P < 0.05

S

:2 25

40

~~

~

__

~

~

CLcR (ml/min)

5 O~

o

_ _--L_ _ _ 20

~

__

40

~~

SO

__

~.

80

CLcR (ml/min)

Fig. 3. Relationships between creatinine clearance and pharmacokinetic parameters of famotidine in patients with renal insufficiency. Abbreviations: Vss == apparent volume of distribution at steady-state; tl;'p == terminal half-life; CL == total body clearance; CLR = renal clearance; CLNR == nonrenal clearance; CLcR == creatinine clearance (data from Takabatake et a!. 1985; Halstenson et a!. 1987; Lin et a!. 1988; Gladziwa et a!. 1988; see table III).

portion to creatinine clearance (CLCR) [see section 3.2.1 and fig. 3]. The CLR was independent of dose after oral administration of famotidine 5 to 40mg in healthy volunteers (Yeh et al. 1987), suggesting that the renal tubular secretion of the drug would not be saturable at a standard or usual therapeutic dose. However, a previous study (Howard et al. 1985)

has shown that about 5 to 10 times larger doses (e.g. famotidine 80 to 480 mg/day) may be required to inhibit gastric secretion in patients with Zollinger-Ellison syndrome. At present, it remains to be determined whether the CLR of famotidine would be saturable at such an extremely high dose, because the renal tubular secretion of the drug is saturable at a plasma dtug concentration of about

184

20 mg/L or greater in rats (Lin et al. 1987c). The biliary or faecal elimination of famotidine has not been studied in humans. 2.2 Plasma Protein Binding Famotidine is only weakly bound to plasma protein (Kroemer & Klotz 1987; Yeh et al. 1987). The protein-bound fraction determined by membrane dialysis in plasma spiked with the drug at a concentration of 50 to 500 ~g/L ranged from 12.3 to 18.3%; in vivo bound fractions assessed in plasma obtained from 5 healthy subjects who had received famotidine 40mg orally ranged from 9.6 to 28.3% at a drug concentration of 42.6 to 155.0 ~g/L (Yeh et al. 1987). In addition, the plasma protein binding of famotidine is concentration independent at the abovementioned, clinically attainable concentration ranges. The fact that famotidine binds weakly to plasma protein implies that it would have a low drug interaction potential at plasma protein binding site(s). To date, no results suggesting a possible drug interaction with other therapeutic agents at protein binding site(s) have, to the authors' knowledge, been reported. 2.3 Pharmacokinetics After Single Oral Doses After oral administration of famotidine, plasma drug concentrations reach Cmax at a time (t max) of around 1.9 to 3.7h postdose (Barzaghi et al. 1989; Inotsume et al. 1989; Kroemer & Klotz 1987; Lin et al. 1987b; Yeh et al. 1987). Following oral administraton of famotidine at a dose range of 5 to 40mg, the Cmax, area under the plasma concentration-time curve (AUC) and amount of unchanged drug excreted into the urine (Ae) were largely dose related (Yeh et al. 1987), suggesting that the oral bioavailability of the drug is dose independent. The tlj2ti of the drug observed after a single oral dose ranged from 2.5 to 3.5h in healthy volunteers (table II). In addition, no discernible differences were observed in relative bioavailability among the 3 dosage formulations (tablet, capsule and suspension) of the drug (Yeh et al. 1987).

Clin. Pharmacokinet. 21 (3) 1991

Famotidine is incompletely absorbed after oral administration, due probably to its low lipid solubility (see section 1). Following an oral dose of radiolabelled famotidine in 4 healthy subjects, 38 and 51 % of the radioactivity was recovered in the urine and faeces, respectively, within 96h (Yeh et al. 1987). Table II lists the mean oral pharmacokinetic parameters of famotidine obtained from healthy volunteers following a single oral dose. Regardless of the formulation (tablet or capsule) the absolute oral bioavailability ranged from 40 to 49%, based on the plasma AUCs (Kroemer & Klotz 1987; Yeh et al. 1987). The oral bioavailability of famotidine estimated from the Ae was also comparable with that estimated from the plasma AUC (Inotsume et al. 1989; Yeh et al. 1987). Food does not appear to affect the bioavailability of famotidine (Lin et al. 1987b). However, Lin et al. (1987b) and Barzaghi et al. (1989) have shown that coadministration of a potent antacid with a neutralising capacity of 150 mEq (,Mylanta II' 30ml) reduced the Cmax and AUC of famotidine by 20 to 30% compared with the values obtained after the administration of famotidine alone. However, the coadministration did not affect the t max of oral famotidine. It remains unclear whether a 20 to 30% reduction in the bioavailability of famotidine by such means would have any clinical implication. No significant drug interaction was observed when the antacid was ingested 2h after the famotidine dose (Barzaghi et al. 1989). 2.4 Pharmacokinetics During Multiple-Dose Administration Although famotidine is often administered for an extended period in the treatment and prevention of peptic ulcer disease, little information is available on its pharmacokinetic behaviour during multiple-dose administration. During repeated oral administration of famotidine 20mg 3 times daily, Cmax and trough plasma concentrations (Cmin) of the drug were largely constant (i.e. about 100' and 50 ~g/L, respectively) over 8 weeks in heathy volunteers (unpubli.shed data on file, Yamanouchi Pharmaceutical Co.). Morgan and Stambuk (1986)

Pharmacokinetics of Famotidine

185

Table II. Mean pharmacokinetic parameters of orally administered famotidine in healthy volunteers Reference

Yeh et al. (1987)

Kraemer & Klotz (1987) Lin et al. (1987b) Barzaghi et al. (1989) Inotsume et al. (1989)

Age (y)

No. of subjects

Dose (mg)

Formulation

NA NA NA NA NA NA NA NA NA 35

15 15 15 16 16 15 15 15 16 6

5 10 20 20 20 40 40 40 40

Capsule Capsule Capsule Capsule Tablet Suspension Capsule Tablet Tablet NA

NA

17

40

8 6 10

22-27 23 66

Cmax WIlL)

t max (h)

t'126 (h)

CLR (L/h)

14.0 32.7 43.4 78.7 78.9 97.3 75.5 88.9 109.3 103.5

2.3 1.9 2.3 2.2 2.4 2.3 1.9 2.0 2.3 2.3

NA 2.5 2.6 3.0 3.5 3.0 2.6 3.3 3.3 3.6

23.9 16.6 18.7 14.8 13.0 22.9 18.6 19.2 20.8

Tablet

81.1

2.6

40

Tablet

156.0

2.8

2.4

20 20

Tablet Tablet

70.1 98.3

2.3 3.7

3.0 6.7

40

F (%)

49.0 45.0

42.0 39.6

25.8

a Urine collection period. Abbreviations: Cmax = peak plasma drug concentration; tmax = time to Cmax; t'126 = terminal plasma half-life; CLR F = bioavailability; Ae = amount of unchanged drug excreted in urine (% dose); NA = not available.

reported that no significant accumulation was observed in famotidine Cmin not only in healthy volunteers but also in cirrhotic patients with normal renal function during repeated oral administration offamotidine 40 mg/day over 7 days. Thus, there appears to be no firm evidence indicating that the pharmacokinetics of famotidine could be nonlinear during a long term dosage regimen. Nonetheless, further studies are definitely required to assess its more detailed pharmacokinetic characteristics during multiple-dose administration.

3. Effect of Age and Disease State on Pharmacokinetics 3.1 Age The pharmacokinetic disposition of famotidine in healthy elderly volunteers has been studied by Lin et al. (1988) after intravenous infusion and by Inotsume et al. (1989) after oral administration (tables I, II). Lin et al. (1988) showed that the el-

Ae (%) [time (h)]a 27.4 [0-72] 27.7 [0-72] 23.7 [0-72] 31.8 [0-72] 27.6 [0-72] 25.4 [0-72] 19.5 [0-72] 23.9 [0-72] 31.2 [0-72]

9.9 [0-12]

44.0 [0-24]

= renal clearance;

derly group (65 to 74 years) had a famotidine CL about 50% less (0.19 L/h/kg) than the young group (23 to 32 years, 0.39 L/hfkg). They have also shown that the age-related reduction in CL of the drug was largely attributable to a change in CLR rather than in nonrenal clearance (CLNR). The elderly patients also had a significantly prolonged t'l2,8 of the drug (4.1h) compared with the young volunteers (2.9h) [Lin et al. 1988]. When a retrospective analysis is made of the data reported in the cumulative literature sources (table I), a significant negative correlation (p < 0.05; r = -0.764) exists between age and famotidine CL (fig. 2). The reason for the elderly group having a reduced CL and CLR of famotidine is most likely to be an age-related reduction in renal plasma flow, glomerular filtration rate or renal tubular function, and/or a combination thereof (Davis & Shock 1950). No data are available on the oral bioavailability of famotidine in the elderly. Because Somogyi et al. (1980) have shown that the Vd of cimetidine reduces in proportion to age,

186

it is of interest to ask if the same is true of famotidine. Although no systematic studies have been made, a retrospective analysis of the data listed in table I suggests that the Vd of famotidine may decrease with aging (fig. 2). However, it remains unclear whether such an age-related change would have any clinical implication. Kraus et al. (1990) studied the pharmacokinetics of famotidine in 10 paediatric patients aged 2 to 7 years with normal renal function during a convalescent period of cardiac surgery. The mean intravenous pharmacokinetic parameters obtained from these patients were largely comparable with those obtained from healthy adult volunteers (Kroemer & Klotz 1987; Lin et al. 1988; Takabatake et al. 1985). At present, no data are available on the pharmacokinetic parameters of famotidine in neonates or infants. 3.2 I>isease State 3.2.1 Renal Insufficiency Because famotidine is mainly eliminated via the kidneys as discussed earlier, patients with renal insufficiency are expected to have a diminished CLR (and CL, because CL "" CLH + CLR, where CLH is the hepatic or metabolic clearance) and a prolonged t,/z,3. Previous studies (Halstenson et al. 1987; Lin et al. 1988; Takabatake et al. 1985) have shown that in patients with renal insufficiency both CL and CLR of famotidine were reduced in proportion to their individual CLCR. In patients with severe renal insufficiency (i.e. CLCR < 10 ml/min) the CL of famotidine was reduced to a value of less than 5 L/h and the t,/z,3 was prolonged to a range of 12 to 27h. The pharmacokinetic parameters of intravenous famotidine in patients with renal insufficiency are listed in table III. When the mean parameters obtained from each of the study groups are plotted against the mean CLCR in the respective groups, a significant correlation is observed (fig. 3). However, the Vss of famotidine does not appear to be altered by renal insufficiency. The reason CLCR correlates with CLNR (or CLH) [fig. 3] is currently unclear and unexplainable, because hepatic oxidative drug me-

Clin. Pharmacokinet. 21 (3) 1991

tabolism is increased in chronic uraemic patients (Maddocks et al. 1975) and is normal or occasionally enhanced in patients with chronic renal insufficiency (Lichter et al. 1973). Taken together, previous studies (Halstenson et al. 1987; Lin et al. 1988; Takabatake et al. 1985) strongly suggest that the maintenance dosage of famotidine for patients with renal insufficiency should be reduced according to the individual CLcR. In fact, Takabatake et al. (1985) have recommended that the dosage of famotidine for patients with moderate (CLCR 35 to 70 ml/min/ 1.73m2) and severe (CLCR < 35 ml/min/1.73m2) renal insufficiency be reduced by 50 and 25%, respectively, from standard levels. Hachisu et al. (1988) examined the validity of this dosage recommendation in 13 patients with severe renal insufficiency undergoing haemodialysis 3 times a week. They found that an oral administration of famotidine 20mg after every haemodialysis session (60 mg/week) produced a mean steady-state, prehaemodialysis plasma drug concentration (CSS) of about 50 /-Lg/L throughout a 4-month study period. 3.2.2 Liver Cirrhosis The pharmacokinetic disposition of famotidine in patients with liver disease has been studied after single intravenous and oral doses in patients with compensated and decompensated liver cirrhosis (Morgan & Stambuk, 1986). Although no significant difference was observed in any of the pharmacokinetic parameters between healthy volunteers and patients with either compensated or decompensated liver cirrhosis, the mean CL of the drug obtained from patients with decompensated liver cirrhosis (16.7 L/h) tended to be lower than that obtained from patients with compensated liver cirrhosis (21.2 L/h) and healthy volunteers (24.8 L/h). Because only a small number of volunteers or patients (n = 5 or 6 in each group) were studied, a possibility exists that a type II (or (3) error might have concealed a difference in the CL among the study groups. All cirrhotic patients in this study appeared from their serum creatinine concentrations to have normal renal function. Obviously, further studies are required to determine if patients

Pharmacokinetics of Famotidine

187

Table III. Mean pharmacokinetic parameters of intravenously administered famotidine in patients with renal insufficiency

Reference

No. of patients

CLCR (ml/min)

V••

tV2~

(L/kg)

(h)

CL (L/h)

CLR (L/h)

CLNR (L/h)

9 5 10

73.8 8 49.28 10.38

1.26 1.42 1.48

2.92 4.72 12.07

22.9 14.5 5.0

15.8 9.4 1.3

7.02 5.10 3.78

Halstenson et al. (1987)

6 6 6

47.1 27.2 Anuric

0.92 0.82 1.05

9.3 9.7 18.7

6.5 4.2 2.5

4.2 1.5

2.32 2.64 2.50

Lin et al. (1988)

7 5 6

48.0 22.7 Anuric

0.96 0.95 1.21

8.4 10.7 17.9

0.089 b 0.061b 0.050 b

0.053 b O.017 b

0.037 b 0.044b

6

<5

1.30

27.2c

2.01

Takabatake et al. (1985)

Gladziwa et al. (1988)

0.05Qb

ml/min/1.48 m2 . L/h/kg. This mean value observed during the dialysis-free interval was reduced to 13.7 ± 5.6h (mean ± SO) during a continuous haemofiltration. which is fairly comparable to the 16.3 ± 4.0h observed during arteriovenous haemofiltration by Saima et al. (1990). Abbreviations: CLCR = creatinine clearance; V•• = volume of distribution at steady-state; tVz~ = terminal plasma half-life; CL = total body clearance; CLR = renal clearance; CLNR = nonrenal clearance. a b c

with decompensated liver cirrhosis would have a reduced famotidine CL compared with patients without liver disease or those with compensated cirrhosis.

4. Haemodialysis and Haemofiltration 4.1 Haemodialysis Because famotidine has a relatively small molecular weight (337.4D), low plasma protein binding «20%) and a fairly small Vd (Kroemer & Klotz 1987; Yeh et al. 1987), it may be assumed that it can be removed by various blood purification methods. Gladziwa et al. (1988) studied the haemofilterability offamotidine in 4 patients with severe renal insufficiency, and found that haemodialysis performed with polysulphone membrane (1.25m 2) and cuprophan membrane (1.3m 2 ) for about 5h removed 16 and 6% of an intravenous dose of famotidine 20mg, respectively. They also studied the removal of famotidine by continuous ambulatory peritoneal dialysis (CAPO) in 4 patients and found that only 4.5% of a similar dose was

recovered in 24h dialysate. Because the dialysability of famotidine by both methods is low, no supplemental dose(s) of the drug would be required after these blood purification procedures. No data are available regarding haemodialysis or CAPDrelated changes in the pharmacokinetic parameters (e.g. clearance) of famotidine. 4.2 Haemofiltration Both intermittent and continuous arteriovenous haemofiltration is widely used as an alternative to haemodialysis. The haemofilterability of famotidine has been studied by 2 groups of investigators, Gladziwa et al. (1988) and Saima et al. (1990). Gladziwa et al. (1988) showed that continuous arteriovenous haemofiltration (CA VH) with polysulphone membrane (1.35m 2) performed at a filtration flow rate (Q:-) of 10 to 15 ml/min for 24h removed 16% of an intravenous dose of famotidine 20mg. They also showed that intermittent haemofiltration performed with a polyacrylonitrile

188

membrane (1.4m 2) at a greater & of 85 mljmin for about 4h removed 8% of the administered dose. Saima et al. (1990) studied the haemofiltration pharmacokinetics of famotidine during intermittent haemofiltration, and found that the sieving coefficient (an index of haemofilterability) of famotidine was largely constant over a & of 3.9 to 29.5 mljmin and that the haemofiltration clearance (CLHF) of the drug was significantly (p < 0.01) correlated with & (i.e. CLHF = 0.78 X & + 0.25, r = 0.90). They estimated that the CLHF of famotidine at a commonly used & of 6 to 12 mlj min for a 24h CAVH would range from 4 to 9 mlj min (Saima et al. 1990), which corresponds to only 10 to 25% of the CL observed in anuric patients (about 35 mljmin) [Gladziwa et al 1988]. In this context, the removal of famotidine by both intermittent and continuous haemofiltration is considered to be clinically insignificant, and therefore no supplemental doses would be required after either of the procedures.

5. Dose- or Concentration-Response Relationship 5.1 Dose- or Concentration-Antisecretory Response Relationship Ryan et al. (1-987) studied the antisecretory profile offamotidine with various oral dosages (lO, 20 and 40mg twice daily at 9am and 9pm) in 10 healthy volunteers and observed that both basal nocturnal and meal-stimulated gastric secretions were suppressed in a dose-related fashion. They also observed a significant association between mean plasma concentrations of famotidine and mean inhibition of meal-stimulated acid secretion. However, the observation that a considerable interindividual variability existed in the relationship between plasma famotidine concentration and gastric acid inhibition did not permit individual plasma concentrations of the drug to be used to predict the antisecretory effect (Ryan et al. 1987). Schepp et al. (1985) studied the in vitro concentration-antisecretory response relationship of famotidine using isolated rat parietal cells. They found that a famotidine concentration of about 20

Clin. Pharmacokinet. 21 (3) 1991

IJ.g/L in the cell medium was associated with a 50% suppression (ICso) of the histamine-induced acid secretion from the parietal cells. Miwa and colleagues (1984) were the first to study the relationship between plasma famotidine concentration and antisecretory effect in humans. They found that a plasma famotidine concentration of 13 IJ.g/L was ICso of the pentagastrin-stimulated gastric acid secretion. Burland et al. (1975) and Lebert et al. (1981) have also shown that the ICso values of cimetidine and ranitidine were about 500 and 165 IJ.gfL, respectively, under similar experimental conditions in humans. On the basis of these findings, famotidine may be considered to be about 40 and 10 times greater in terms of its antisecretory potency than cimetidine and ranitidine, respectively. However, because the concentrationresponse relationships of H2-receptor antagonists have been evaluated from the pooled or overall data obtained from healthy volunteer or patient groups in the earlier studies (Burland et al. 1975; Lebert et al 1981; Miwa et al. 1984), no information appears to be available on the intersubject variability in the anti secretory response to each of the drugs. Intersubject variability in the antisecretory response to famotidine has been studied by Echizen et al (1988), who continuously monitored plasma drug concentrations versus intragastric pH using a microelectrode over 6 to 8h after intravenous administration of the drug to healthy volunteers and patients with upper gastrointestinal bleeding. Because there was a reasonably good sigmoidal relationship between plasma drug concentrations and intragastric pH in both the study groups (fig. 4), the concentration-response relationship of the drug was analysed by the sigmoidal maximum effect (Emax) model (Holford & Sheiner 1981) which allowed an estimate of the individual maximum antisecretory response to the drug assessed as Emax and the sensitivity to the drug as a plasma drug concentration associated either with a 50% of Emax (ECso) or with an intragastric pH of 4 (ECp H4). There were no significant differences in both the magnitude (Emax) and the sensitivity (ECso and ECp H4) of the antisecretory response to famotidine between healthy volunteers and patients with up-

Pharmacokinetics of Famotidine

Volunteer

10

(3)

8 :I:

..

(1) --~~

O.

Q.

~

189

(2)

6

10

01

~

.E

4 2

•

(6)

(0.5)

, 20

, 10

10

, , , " 40

60

80 100

5.2 Therapeutic Implications of Concentration-Response Data

Patient

8 :I:

Q.

U

i

6

10

01

i

4

•

2

(0.5)

, 10

24.8 ± 10.3 and 17.7 ± 10.7 !J.g/L, respectively. While the Emax was fairly constant, there was a large intersubject variation in sensitivity to the antisecretory effect (i.e. ECpH4). These findings would explain, at least to some extent, why previous attempts have been unsuccessful in correlating plasma concentrations of H2-receptor antagonists with suppression of gastric acid output, based on the pooled data from a relatively small number of subjects and patients (Longstreth et al 1976; Runne et at 1979; Ryan et at 1987).

, 20

, 40

,

, , , " 60

80 100

Plasma famotidine conc. ("gIL)

Fig. 4. Relationship between plasma famotidine concentrations and intragastric pH analysed by the sigmoidal maximum effect (Emax) model (Holford & Sheiner 1981) in a healthy volunteer and in a patient with upper gastrointestinal bleeding. Numbers in parentheses represent sampling times in hours after an intravenous infusion offamotidine 0.1 mgl kg over 5 min. Note the presence of a counterclockwise hysteresis in the plasma concentration-response relationship; • = plasma drug concentrations measured; 0 = plasma drug concentrations estimated by means of the pharmacokinetic parameters obtained from the respective subjects. The estimated values for Emax , the plasma concentration at 50% of Emax (ECso) and the concentration associated with an intragastric pH of 4 (ECp H4) were pH 7.3, 26.0 "giL, and 25.4 "giL in the healthy volunteer and pH 7.8, 32.6 "giL, and 28.9 "giL in the patient, respectively (from Echizen et al. 1988, with permission).

per gastrointestinal bleeding: the mean (± SD) Emax values obtained from healthy volunteers and from patients with upper gastrointestinal bleeding were 7.2 ± 0.2 and 7.4 ± 0.5 w,/L and the mean plasma drug concentration values for ECpH4 were

Many controlled clinical trials have clearly demonstrated that the suppression of gastric acid secretion by famotidine and other H2-receptor antagonists promotes the healing rate of gastric and duodenal ulcer (Campoli-Richards & Clissold 1986; Langtry et at 1989). However, it is still unclear if and to what degree an anti secretory effect of the drugs assessed by the supression of gastric acid output or by intragastric pH monitoring would be desirable for maximising ulcer-healing effectiveness. Nonetheless, recent studies have emphasised the importance of maintaining a high intragastric pH (i.e. >3.5) in preventing stress-induced ulceration and haemorrhagic (or erosive) gastritis in critically ill patients (Hastings et at 1978; Priebe et al 1980). Using the concentration-response relationship of famotidine obtained from previous studies (Echizen et a1. 1988; Miwa et at 1984), it is possible to estimate an infusion dose or rate for attaining around-the-clock control of a high intragastric pH (e.g. >pH 3.5) in the abovementioned clinical conditions. For instance, assuming that a 70kg patient with upper gastrointestinal bleeding has a famotidine CL of 25 L/h, a continuous infusion at a rate of 1.25 mg/h or 30 mg/day would produce a famotidine CSs of around 50 !J.g/L [which exceeds the upper limit of the 95% confidence interval for ECpH4, obtained from patients with upper gastrointestinal bleeding (Echizen et at 1988)], thereby possibly attaining a high intragastric pH (>4) throughout the infusion period. However, further

190

clinical studies are required to justify the validity of such an assumptive dosage guideline for preventing stress-induced gastroduodenal mucosal lesions in critically ill patients. It remains to be determined whether any clinical condition (e.g. chronic renal failure, liver cirrhosis) would alter target organ sensitivity to an H2receptor antagonist. Studies (Martyn et al. 1989; Walker et al. 1989) suggested that paediatric patients with burn injuries and adult patients with liver cirrhosis appear to be resistant to the antisecretory effect of cimetidine. However, it is not known whether the apparent resistance to the antisecretory effect of the drug in these patients should be attributed to a pharmacokinetic mechanism(s) [e.g. an increased CL] or pharmacodynamic mechanism(s) [e.g. an increased ICso for gastric acid secretion], or a combination thereof. Therefore, attempts should be made to investigate the pharmacokinetic-pharmacodynamic relationship of famotidine and other H2-receptor antagonists under these clinical conditions.

6. Drug Interaction Potential Because H2-receptor antagonists enjoy a huge market and are widely used in clinical practice, they will continue to be prescribed concomitantly with diverse therapeutic agents. Therefore, clinicians should be aware of clinically relevant pharmacokinetic and pharmacodynamic interactions between famotidine and other widely prescribed drugs, or drugs more likely to be prescribed concomitantly with famotidine. From the data reported to date, famotidine appears to possess a lower drug interaction potential than the 2 earlier agents cimetidine (Baciewicz & Baciewicz 1989; Kirch et al. 1984; Powell & Donn 1984) and ranitidine (Baciewicz & Baciewicz 1989; Gerber et al. 1985; Grant et al. 1989; Powell & Donn 1984; Somogyi & Muirhead 1987), with regard not only to hepatic drug metabolism but also to renal drug elimination.

Clin. Pharmacokinet. 21 (3) 1991

6.1 Hepatic Metabolism It is generally believed that cimetidine binds to cytochrome P450 and then produces a stable cytochrome-substrate complex which prevents the access of other agents to the cytochrome P450 enzyme system (Gerber et al. 1985; Powell & Donn 1984; Rendic et al. 1979). In in vitro experiments with human liver microsomes, Pasanen et al. (1986) and Wang et al. (1988) have shown that famotidine did not bind to cytochrome P450 at a drug concentration of up to 4 mmol/L or l.35 giL. In addition, famotidine did not inhibit the activity of any ofthe human hepatic P450 isozymes (i.e. arylhydrocarbon-hydroxylase, 7-ethoxycoumarin-Odesethylase and 7-ethoxy-resorufin-O-desethylase) studied in vitro (Pasanen et al. 1986; Wang et al. 1988). Table IV summarises the data obtained from in vivo human studies examining a possible drug interaction between famotidine and other therapeutic drugs. The data suggest that famotidine affects neither the disposition of several model drugs with a capacity-limited (i.e. low CL) hepatic drug metabolism [e.g. phenazone (antipyrine), diazepam, theophylline] nor that of some drugs with a flow-dependent (i.e. high CL) hepatic drug metabolism which are altered by cimetidine or ranitidine (see reviews by Baciewicz & Baciewicz 1989; Brogden et al. 1982; Gerber et al. 1985; Grant et al. 1989; Kirch et al. 1984; Powell & Donn 1984; Somogyi & Gugler 1983; Somogyi & Muirhead 1987). It has been also shown that famotidine altered neither the hepatic blood flow estimated by indocyanine green CL (Ohnishi et al. 1987; Testa et al. 1987) nor the portal blood flow measured by the ultrasonic duplex system in healthy volunteers and in patients with biopsy-proven chronic hepatitis (Ohnishi et al. 1987). To date, it is not known whether famotidine would alter nonoxidative hepatic drug metabolism (e.g. glucuronide conjugation) in humans.

6.2 Renal Excretion Cimetidine inhibits the renal elimination of various cationic drugs (e.g. procainamide) and creatinine (Baciewicz & Baciewicz 1989; Burgess et al.

Pharmacokinetics of Famotidine

Table IV. Drugs reported to interact with cimetidine or ranitidine (see reviews listed in text) but not with famotidine Elimination route

Reference

Hepatic metabolism Low-c/earance (capacity-limited) drugs Alcohol 8 Tanaka & Nakamura (1988); Holtmann & Singer (1988) Somerville et al. (1986) Aminophenazone (aminopyrine)8 Locniskar et al. (1986) Desmethyldiazepam 8 Klotz et al. (1985); Locniskar et al. Diazepam 8 (1986) Phenazone (antipyrine)8 Somerville et al. (1986); Staiger et al. (1984) Zimmermann et al. (1987) Phenprocoumon Phenytoin 8 Sambol et al. (1989) Theophylline8 Lin et al. (1987a); Verdiani et al. (1988) Warfarin 8 Humphries (1987) High-clearance (flow-dependent) drugs Indocyanine greena.b Ohnishi et al. (1987); Sambol et al. (1989); Testa et al. (1987) Renal excretion Acecainide (NKlotz et al. (1985) acetylprocainamide)8,b Creatinine8 Abraham et al. (1987) Procainamide 8,b Klotz et al. (1985) a b

Inhibited by cimetidine. Inhibited by ranitidine.

1982; Gerber et al. 1985; Powell & Donn, 1984; Somogyi & Muirhead 1987) by competing with these substances at the site of renal tubular secretion. Because famotidine is a cationic drug and excreted into the urine via active renal tubular secretion (Lin et al. 1987c; Takabatake et al. 1985), it is also assumed, on theoretical grounds, to interfere with the excretion of other cationic drugs or endogenous substances. However, Abraham et a1. (1987) and Klotz et a1. (1985) showed that famotidine did not inhibit the renal elimination of procainamide, acecainide (N-acetylprocainamide) and creatinine. There remains, however, a possibility that famotidine is excreted via a mechanism using a different cation transport system from that for cimetidine and other cationic drugs. It may also be plausible that plasma concentrations attained

191

by a usual therapeutic dose (e.g. famotidine 20mg twice daily) would be too low to cause significant competition with other drugs at the site of renal tubular secretion. In any event, because only a small number of drugs which might interact with famotidine have been studied, it is premature to draw firm conclusions regarding the drug interaction potential of famotidine at a pharmacokinetically mechanistic level of renal drug disposal.

7. Conclusions and Therapeutic Implications H2-Receptor antagonists have opened a new era in the treatment and prevention of peptic ulcer disease and allied clinical conditions. Although cimetidine, the first H2-receptor antagonist introduced into clinical practice, is generally safe and well tolerated, clinical experience has revealed that it has an ancillary pharmacological property leading to a greater incidence of untoward side effects compared with more recently developed H2-receptor antagonists: cimetidine has been shown to inhibit hepatic oxidative drug metabolism at the usual therapeutic dosage, and to produce an antiandrogenic effect at higher dosages (McGuigan 1981). Ranitidine is more potent than cimetidine and has been claimed to be devoid of drug interaction potential and antiandrogenic property (Brogden et al. 1982; Grant et al. 1989). However, the relative safety ofranitidine compared with cimetidine, particularly in terms of drug interaction potential, appears to have been gradually revised (Baciewicz & Baciewicz 1989; Kirch et al. 1984). In this context, famotidine may have certain advantages over the 2 H2-receptor antagonists developed earlier in terms of its higher antisecretory potency and lower drug interaction potential. Nevertheless, because clinical experience with famotidine is still limited, it is premature to draw a definite conclusion on the relative safety offamotidine compared with the earlier H2-receptor antagonists, cimetidine and ranitidine. From a pharmacokinetic point of view, further studies are definitely required to examine the pharmacokinetic characteristics of famotidine during multiple-dose administration in patients with renal

192

insufficiency or with liver cirrhosis, and in elderly patients, whose pharmacokinetic disposition profiles for many drugs are known to be altered. The pharmacokinetic characteristics of famotidine should also be studied under other clinical conditions (e.g. burn injury), where the disposition of earlier H2-receptor antagonists has been shown to be altered (Martyn et al. 1989). From a pharmacodynamic point of view, attempts should be made to study a possible alteration of target organ sensitivity to the drug in diverse clinical conditions (e.g. Zollinger-Ellison syndrome, liver cirrhosis, burn injury) where apparent resistance to the drug has been reported (Martyn et al. 1989; Walker et al. 1989). Finally, numerous comparative clinical trials (see the reviews by Campoli-Richards & Clissold 1986; Langtry et al. 1989) have shown that the currently available H2-receptor antagonists have a similar antiulcer effect. Thus, attempts should be made to assess the cost-effectiveness and risk-benefit relationships of famotidine versus each of the earlier agents in the treatment and prevention of peptic ulcer disease and allied clinical conditions such as upper gastrointestinal bleeding.

Acknowledgements The authors would like to thank Mrs Mitsuko Echizen for her secretarial assistance in preparing the manuscript, and Drs Shigeki Saima and Keiko Yoshimoto for providing unpublished data. The authors' studies cited in this review article were partly supported by a grant-inaid from the Ministry of Human Health and Welfare, Japan.

References Abraham PA, Opsahl JA, Halstenson CE, Chremos AN, Matzke GR, et al. The effect of famotidine on renal function in patients with renal insufficiency. British Journal of Clinical Pharmacology 24: 385-389, 1987 Baciewicz AM, Baciewicz FA. Effect of cimetidine and ranitidine on cardiovascular drugs. American Heart Journal 118: 144154, 1989 Baron JH. Current views on pathogenesis of peptic ulcer. Scandinavian Journal of Gastroenterology 80: 1-10, 1982 Barzaghi N, Gatti G, Crema F, Perucca E. Impaired bioavailability of famotidine given concurrently with a potent antacid. Journal of Clinical Pharmacology 29: 670-672, 1989 Brogden RN, Carmine AA, Heel RC, Speight TN, Avery GS. Ranitidine: a review of its pharmacology and therapeutic use

Clin. Pharmacokinet. 21 (3) 1991

in peptic ulcer disease and other allied diseases. Drugs 24: 267303, 1982 Burgess E, Blair A, Krichman K, Cutler RE. Inhibition of renal creatinine secretion by cimetidine in humans. Renal Physiology 5: 27-30, 1982 Burland WL, Duncan WAM, Hesselbo T, Mills JG, Sharpe PC, et al. Pharmacological evaluation of cimetidine, a new histamine H2-receptor antagonist, in healthy man. British Journal of Clinical Pharmacology 2: 481-486, 1975 Campoli-Richards DM, Clissold SP. Famotidine: pharmacodynamic and pharmacokinetic properties and a preliminary review of its therapeutic use in peptic ulcer disease and Zollinger-Ellison syndrome. Drugs 32: 197-221, 1986 Carlucci G, Biordi N, Napolitano T, Bologna M. Determination of famotidine in plasma, urine and gastric juice by high-performance liquid chromatography using disposable solid-phase extraction columns. Journal of Pharmaceutical and Biomedical Analysis 6: 515-519, 1988 Courtney TP, Shaw RW, Cedar E, Mann SG, Kelly JG. Excretion offamotidine in breast milk. Abstract. British Journal of Clinical Pharmacology 26: 639P, 1988 Dammann HG, Muller P, Simon B, Lommerell B. 24 hour intragastric acidity and single nighttime dose of three H2-blockers. Lancet 2: 1078, 1983 Davis DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow and tubular excretory capacity in adult males. Journal of Clinical Investigation 29: 496-507, 1950 Dicke JM, Johnson RF, Henderson GI, Kuehl n, Schenker S. A comparative evaluation of the transport of H2-receptor antagonists by the human and baboon placenta. American Journal of Medical Sciences 295: 198-206, 1988 Echizen H, Shoda R, Umeda N, Ishizaki T. Plasma famotidine concentration versus intragastric pH in patients with upper gastrointestinal bleeding and in healthy subjects. Clinical Pharmacology and Therapeutics 44: 690-698, 1988 Gerber MC, Tejwani GA, Gerber N, Bianchine JR. Drug interactions with cimetidine: an update. Pharmacology and Therapeutics 27: 353-370, 1985 Gladziwa U, Klotz U, Krishna DR, Schmitt H, Glockner WM, et al. Pharmacokinetics and dynamics of famotidine in patients with renal failure. British Journal of Clinical Pharmacology 26: 315-321, 1988 Grant SM, Langtry HD, Brogden RN. Ranitidine: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer disease and other allied diseases. Drugs 37: 801-870, 1989 Hachisu T, Yokoyama T, Oda Y, Ando K, Hattori Y, et al. Optimal therapeutic regimen of famotidine based on plasma concentrations in patients with chronic renal failure. Clinical Therapeutics 6: 656-663, 1988 Halstenson CE, Abraham PA, Opsahl JA, Chremos AN, Keane WF, et al. Disposition of famotidine in renal insufficiency. Journal of Clinical Pharmacology 27: 782-787,1987 Hastings PA, Skillman 11, Bushnell LS, Silen W. Antacid titration in the prevention of acute gastrointestinal bleeding: a controlled randomized trial in 100 critically ill patients. New England Journal of Medicine 298: 1041-1045, 1978 Holford NGH, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clinical Pharmacokinetics 6: 429-453, 1981 Holtmann G, Singer MV. Histamine H2-receptor antagonists and blood alcohol levels. Digestive Diseases and Sciences 33: 767768, 1988 Howard JM, Chremos AN, Collen MJ, McArther KE, Cherner JA, et al. Famotidine, a new, potent, long-acting histamine H2receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 88: 1026-1033, 1985 Humphries n. Famotidine: a notable lack of drug interactions.

Pharmacokinetics of Famotidine

Scandinavian Journal of Gastroenterology 134 (Suppl.) 55-60, 1987 Inotsume N, Nishimura M, Fujiyama S, Sagara K, Sato T, et al. Pharmacokinetics of famotidine in elderly patients with and without renal insufficiency and in healthy young volunteers. European Journal of Clinical Pharmacology 36: 517-520,1989 Kagevi I, Thorhallsson E, Wahlby L. CSF concentration of famotidine. British Journal of Clinical Pharmacology 24: 849850, 1987 Kagevi I, Wahlby L. CSF concentrations of ranitidine. Lancet I: 164-165, 1985 Kawai R, Yamada S, Kawamura S, Miwa T, Miwa M. Pharmacokinetics of famotidine (YM-I I 170), a new histamine Hzreceptor antagonist: Part 2. Absorption and excretion in dogs and humans. Ohyo Yakuri (Pharmacometrics) 27: 73-77,1984 Kirch W, Hoensch H, Janisch HD. Interactions and non-interactions with ranitidine. Clinical Pharmacokinetics 9: 493-501, 1984 Klotz V, Arvela P, Rosenkranz B. Famotidirie, a new Hz-receptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide. European Journal of Clinical Pharmacology, 28: 671-675, 1985 Kraus G, Krishna DR, Chmelarsch D, Schmid M, Klotz V. Famotidine: pharmacokinetic properties and suppression of acid secretion in paediatric patients following cardiac surgery. Clinical Pharmacokinetics 18: 77-81, 1990 Kroemer H, Klotz V. Pharmacokinetics of famotidine in man. International Journal of Clinical Pharmacology, Therapy and Toxicology 25: 458-463, 1987 Langtry HD, Grant SM, Goa KL. Famotidine: an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in peptic ulcer disease and other allied diseases. Drugs 38: 551-590, 1989 Lebert PA, MacLeod SM, Mahon WA, Soldin SJ, Vandenberghe HM. Ranitidine kinetics and dynamics: I. Oral dose studies. Clinical Pharmacology and Therapeutics 30: 539-544, 1981 Lichter M, Black M, Arias 1M. The metabolism of antipyrine in patients with chronic renal failure. Journal of Pharmacology and Experimental Therapeutics 187: 612-619, 1973 Lin JH, Chremos N, Chiou R, Yeh KC, Williams R. Comparative effect of famotidine and cimetidine on the pharmacokinetics of theophylline in normal volunteers. British Journal of Clinical Pharmacology 24: 669-672, 1987a Lin JH, Chremos N, Kanovsky SM, Schwartz S, Yeh KC, et al. Effects of antacids and food on absorption offamotidine. British Journal of Clinical Pharmacology 24: 551-553, 1987b Lin JH, Chremos AN, Yeh KC, Antonello J, Hessey II GA. Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man. European Journal of Clinical Pharmacology 34: 41-46, 1988 Lin JH, Los LE, Vim EH, Duggan DE. Vrinary excretion kinetics of famotidine in rats. Drug Metabolism and Disposition 15: 212-216, 1987c Locniskar A, Greenblatt DJ, Harmatz JS, Zinny MA, Shader RI. Interaction of diazepam with famotidine and cimetidine, two Hz-receptor antagonists. Journal of Clinical Pharmacology 26: 299-303, 1986 Longstreth GF, Go VLW, Malagelada J-R. Cimetidine suppression of nocturnal gastric secretion in active duodenal ulcer. New England Journal of Medicine 294: 801-804, 1976 Maddocks JL, Wake CJ, Harber MJ. The plasma half-life of antipyrine in chronic uraemic and normal subjects. British Journal of Clinical Pharmacology 2: 339-343, 1975 Martyn JAJ, Greenblatt DJ, Hagen J, Hoaglin DC. Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children. European Journal of Clinical Pharmacology 36: 361-367, 1989 McCallum RW, Kuljian B, Chremos AN, Tupy-Vischich MA, Huber PB. MK-208, a novel histamine Hz-receptor inhibitor

193

with prolonged antisecretory effect. Digestive Diseases and Sciences 30: 1139-1144, 1985 McGuigan J. A consideration of the adverse effects of cimetidine. Gastroenterology 80: 181-192, 1981 Miwa M, Tani N, Miwa T. Inhibition of gastric secretion by a new Hz-receptor antagonist. International Journal of Clinical Pharmacology, Therapy and Toxicology 22: 214-217,1984 Morgan MY, Stambuk D. Famotidine pharmacokinetics following oral and intravenous administration in patients with liver disease: results of a preliminary study. Postgraduate Medical Journal 62 (Supp!. 2): 29-37, 1986 Ohnishi K, Saito M, Nomura F, Okuda K, Suzuki N, et a!. Effect of famotidine on hepatic hemodynamics and peptic ulcer. American Journal of Gastroenterology 82: 415-418,1987 Pasanen M, Arvela P, Palkonen 0, Sotaniemi E, Klotz V. Effect of five structurally diverse Hz-receptor antagonists on drug metabolism. Biochemical Pharmacology 35: 4457-4461, 1986 Piper DW. Drugs for prevention of peptic ulcer recurrence. Drugs 26: 439-453, 1983 Powell JR, Donn KH. Histamine Hz-antagonist drug interactions in perspective; mechanistic concepts and clinical implications. American Journal of Medicine 77 (Supp!. 5B): 57-84, 1984 Priebe HJ, Skillman JJ, Bushnell LS, Silen W. Antacid versus cimetidine in preventing acute gastrointestinal bleeding. New England Journal of Medicine 302: 426-430, 1980 Rahman A, Hoffman NE. High-performance liquid chromatographic determination offamotidine in urine. Journal ofChromatography 428: 395-401, 1988 Rendic S, Sunjic V, Toso R, Kajfez F, Ruf HH. Interaction of cimetidine with liver microsomes. Xenobiotica 9: 555-564, 1979 Riley AJ, Crowley P, Harrison C. Transfer of ranitidine to biological fluids: milk and semen. In Misiewcz & Wormsley (Eds) The clinical use of ranitidine, Medicine Publishing Foundation Series, Vol. 5, pp. 77-86, Medicine Publishing Foundation, Oxford, 1982 Rune J, Hesselfeldt P, Larsen N-E. Clinical and pharmacological effectiveness of cimetidine in duodenal ulcer patients. Scandinavian Journal of Gastroenterology 14: 489-492, 1979 Ryan JR, Chremos AN, Vargas R, Mantell G, Johnson CL, et a!. The effect of various dose regimens of famotidine on basal nocturnal and meal-stimulated gastric secretion. Clinical Pharmacology and Therapeutics 42: 225-231, 1987 Saima S, Echizen H, Yoshimoto K, Ishizaki T. Hemofiltrability of Hz-receptor antagonist, famotidine, in renal failure patients. Journal of Clinical Pharmacology 30: 159-162, 1990 Sambol NC, Vpton RA, Chremos AN, Lin ET, Williams RL. A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow. British Journal of Clinical Pharmacology 27: 83-87, 1989 Schentag JJ, Calleri G, Rose JQ, Cerra FB, DeGlopper E, et al. Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion. Lancet I: 177-181, 1979 Schepp W, Miederer SE, Ruoff H-J. Effects of hormones (calcitonin, GIP) and pharmacological antagonists (ranitidine and famotidine) on isolated rat parietal cells. Regulatory Peptides 12: 297-308, 1985 Smith JL, Gamal MA, Chremos AN, Graham DY. Famotidine, a new Hz-receptor antagonist: effect on parietal, nonparietal and pepsin secretion in man. Digestive Diseases and Sciences 4: 308-312, 1985 Somerville KW, Kitchingman GA, Langman MJS. Effect of famotidine on oxidative drug metabolism. European Journal of Clinical Pharmacology 30: 279-281, 1986 Somogyi A, Gugler R. Cimetidine excretion into breast milk. British Journal of Clinical Pharmacology 7: 627-628, 1979 Somoygi A, Gugler R. Clinical pharmacology of cimetidine. Clinical Pharmacokinetics 8: 463-495, 1983 Somogyi A, Muirhead M. Pharmacokinetic interactions of cimetidine 1987. Clinical Pharmacokinetics 12: 321-366, 1987

194

Somogyi A, Rohner H-G, Gugler R. Pharmacokinetics and bioavailability of cimetidine in gastric and duodenal ulcer patients. Clinical Pharmacokinetics 5: 84-94, 1980 Staiger CH, Korodnay B, Devries JX, Weber E, Muller P, et al. Comparative effects of famotidine and cimetidine on antipyrine kinetics in healthy volunteers. British Journal of Clinical Pharmacology 18: 105-106, 1984 Takabatake T, Ohta H, Maekawa M, Yamamoto Y, Ishida Y, et al. Pharmacokinetics of famotidine, a new H2-receptor antagonist, in relation to renal function. European Journal of Clinical Pharmacology 28: 327-331, 1985 Tanaka E, Nakamura K. Effects of H2-receptor antagonists on ethanol metabolism in Japanese volunteers. British Journal of Clinical Pharmacology 26: 96-99, 1988 Teres J, Borda JM, Rimola A, Bru C, Rodes J. Cimetidine in acute gastric mucosal bleeding: results of a double-blind randomized trial. Digestive Diseases and Sciences 25: 92-96, 1980 Testa R, Grasso A, Dagnino F, Ibba R, Varagona G, et al. Famotidine does not affect indocyanine green disposition and serum bile acid levels in healthy subjects. British Journal of Clinical Pharmacology 23: 779-780, 1987 Verdiani P, DiCarlo S, Baronti A. Famotidine effects on theophylline pharmacokinetics in subjects affected by COPD. Chest 94: 807-810, 1988 Vincek WC, Constanzer ML, Hessey GA, Bayne WF. Analytical

Clin. Pharmacokinet. 21 (3) 1991

method for the quantification of famotidine, an H2-receptor blocker, in plasma and urine. Journal of Chromatography 338: 438-443, 1985 Walker S, Krishna DR, Klotz U, Bode Jc. Frequent non-response to histamine H2-receptor antagonists in cirrhotics. Gut 30: 11051109, 1989 Wang RW, Miwa GT, Argenbricht LS, Lu AYH. In vitro studies on the interaction of famotidine with liver microsomal cytochrome P-450. Biochemical Pharmacology 37: 3049-3053, 1988 Wilson JT, Brown RD, Cherek DR, Dailey JW, Hilman B, et al. Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences. Drugs 5: 1-66, 1980 Yeh KC, Chremos AN, Lin JH, Constanzer ML, Kanovsky SM, et al. Single-dose pharmacokinetics and bioavailability of famotidine in man: results of multicenter collaborative studies. Biopharmaceutics and Drug Disposition 8: 549-560, 1987 Zimmermann R, Kramer HJ, Harenberg J, Simon B, Kommerell B (Eds). Famotidine: international symposium, Berlin, 1985, pp. 47-49, Georg Thieme Verlag, Stuttgart, 1987

Correspondence and reprints: Dr Hirotoshi Echizen, Division of Clinical Pharmacology, Clinical Research Institute, National Medical Center, Toyama 1-21-2, Shinjuku-ku, Tokyo 162, Japan.