Clinical Pharmacokinetics 5: 221-245 (1980) 0312-5963/80/0500-0221/$06.25/0 © ADIS Press Australasia Pry Ltd. All rights reserved.

Clinical Pharmacokinetics of Diuretics Bjorn Beermann and Margaretha Groschinsky-Grind Department of Medicine and Clinical Pharmacology Laboratory, Serafimerlasarettet, Stockholm

Summary

Despite extensive use of diuretics, for only a few have their pharmacokinetics been evaluated. Bendroflumethiazide is completely absorbed and uptake from the gastrointestinal tract is not changed by food. Plasma half-life is about 3h. Apparent volume of distribution averages 1.5£/kg. Up to 'two thirds of the drug is eliminated via non-renal routes. " Hydrochlorothiazide is 65 % absorbed in healthy fasting subjects and 75 % absorbed when given with food. The increased uptake appears to be caused by decreased gastric emptying rate. Absorption is impaired in patients who have undergone intestinal shunt surgery and in some patients with cardiac failure. Plasma half-life averages 10h in subjects with normal renal function. It is prolonged in renal failure as the drug is mainly eliminated via the kidneys in ' " unchanged form. The bioavailability of hydroflumethiazide is at least 50 %. Elimination hal/-life is about 17h in normal subjects and IOh in patients with cardiac failure. The drug is largely eliminated unchanged, in the urine. The half-life of poly thiazide is approximately 26h. About 20 % of an oral dose is cleared via the kidneys. Chlorthalidone is 65 % absorbed. Up to 75 % of a dose is bound to'plasmaproteins and extensively to blood cells. Only 1.4 % of the tota'i amount of the drug in blood is found in plasma.' Plasma half-life averages 40 to 65h. Apparent volume of distribution is close to 300£. This diuretic is mainly eliminated in the urine, although it is metabolised to some extent. Bumetanide is completely absorbed. Up to 96 % is bound to plasma proteins. Apparent volume of distribution ranges from 12 to 35£. Plasma hal/-life is 1.2 to J.5h in healthy subjects and does not appear to be prolonged in renal failure. Renal and non-renal clearance contributes equalfY to its elimination. The uptake of frusemide (furosemide) from the gastrointestinal tract is :about 65 % and is decreased in uraemia and nephrosis. Protein binding is 96 to 98 % and is, diminished in nephrosis. Plasma half-life is approximately 50 minutes in healthy subjects and is prolonged about 3 times in renalfailure. Apparent volumeo/distribution (Vd~rangesfrqm J4 to 11£. Urinary excretion and non-renal elimination contribute almost equally to plasma clearance. The uptake of/§...mi/ori~is at least 50 % and is diminished when given with food. Plasma half-life averages IOh. Amiloride is essentially eliminated unchanged in'the urine. '

Clinical Pharmacokinetics of Diuretics

222

Spironolactone and potassium-canrenoate are both metabolised to canrenone which mainly exerts the renal effects of the drugs. The uptake from the gastrointestinal tract is at least 70 and /00 % respectively. The protein binding of canrenone averages 98 %. The half-life of canrenone is 18 to 20h after doses of 100 to 400mg. Canrenone is elimlrlUied as metaboiites via the urine and the bi/e.

The introduction of modern diuretics 2 decades ago was a revolution for the treatment of cardiac failure and hypertension. When loop diuretics were introduced patients with advanced cardiac and renal failure could also be treated effectivelY and allowed to live almost normal lives. However, despite extensive use of this group of drugs most knowledge about the pharmacokinetics of diuretics derives from the last 5 years. Although some of the drugs have been studied extensively there is a complete lack of data about several diuretics. The purpose of this review is to condense the present information on this subject. When data obtained with specific methods of drug assay are available other studies are excluded from the review.Averages are presented as means ± SD unless otherwise indicated.

J. Thiazides and Other Diuretics with Similar Actions 1.1 Bendroflumethiazide (table I)

given with food to 6 volunteers (Beermann et al., I 978c). Bendroflumethiazide is 94 % bound to human albumin at pH 7.3 and 25°C (Agren and Back, 1973).

1.1.2 Plasma Kinetics and Elimination The plasma kinetics after a single oral dose of I Omg bendroflumethiazide could be described according to a I-compartment open model. The terminal elimination phase half-life averaged 3h. The mean value for apparent volume of distribution was 1.5L/kg (Beermann et al., 1977b). Approximately 30 % of a single oral dose at 10mg bendroflumethiazide was excreted unchanged in the urine and renal clearance averaged I 05ml/min. Nonrenal clearance was 260ml/min (mean value) [Beermann et al., 1977b]. 1. J.3 Pharmacokinetics of Bendroflumethiazide in Hypertensive Patients Eight hypertensive patients were treated with 2.5 and 5.0mg of bendroflumethiazide daily for a period of \4 days on each dose level. Before taking the daily

Bendroflumethiazide (fig. I) is one of the most potent thiazides. It is used in doses of 2.5 to IOmg daily. A sensitive GLC assay of the diuretic has been described (Beermann et al., 197 6a).

J. J. J Bioavailability and Binding to Blood Elements Bretell et al. (I964) administered lSS-bendroflumethiazide orally and intravenously to healthy subjects. Identical urinary recovery of radioactivity after the 2 routes of administration indicates complete gastrointestinal uptake of the drug. The uptake of bendroflumethiazide was unchanged when it was

Fig. 1. Structural formu la of bendroflumethiazide.

223

Clinical Pharmacokinetics of Diuretics

Table I. Pharmacokinetic data of bendroflumethiazide after oral administration

Reference b

Subjects' Dosec (n) (mgl

Beermann et al. (1977b)

N (9)

10 Sd

Beermann et al. (1978b)

HT (S)

2.5 Md 5 Md

a b c d

t'12 (h)

3.0±O.5

Volume of distribution (L/kg)

Clearance (ml/min) systemic

renal

non-renal

1.4S±O.41

364± 73

105±24

260± 77

93±25 (n=6) 3.9± 1.Od (n=5)

1.18±O.3l (n=5)

253±4l (n=5)

4S±32 (n=6)

200± 58 (n=5)

N = normal; HT = hypertension. Concentration of bendroflumethiazide was determined with gas liquid chromatography. Md = multiple dosing; Sd = single dosing. Recalculated from authors data.

dose of bendroflumethiazide no trace of bendroflumethiazide was found in plasma. Peak levels were seen after 2.3h and averaged 23 and 50ng/ml after 2.5 and 5.0mg bendroflumethiazide respectively. The plasma half-life after a 5mg dose averaged 3.9h and the apparent volume of distribution 1.2L/kg. Nonrenal clearance was 200ml/ min. Renal clearance of bendroflumethiazide was 48ml/ min which was significantly lower than after 2.5mg bendroflumethiazide, although the· creatinine clearance remained unchanged. This might be explained by the assumption that accumulation of metabolites, perhaps active, during long term treatment would compete with bendroflumethiazide for tubular secretory pathways. An elevated level of urate might also influence the secretion of bendroflumethiazide, as it .does 'the tubular secretion of chlorothiazide in chickens (Beermann et al., 1978d). J. J.4 Relationship between Plasma Levels and Effects No relationship was found between plasma levels of bendroflumethiazide and diuresis after a single oral dose of bendroflumethiazide. During long term treatment of hypertensive patients there was likewise no relationship between plasma levels of bendroflu-

methiazide and antihypertensive effect (Beermann et al., 1977b, I 978d). 1.2 Hydrochlorothiazide (table II) Hydrochlorothiazide (fig. 2) is a thiazide of intermediate potency. It is administered in doses from l2.5mg up to 200mg daily. Various assays for hydrochlorothiazide in biological fluids (plasma, blood corpuscles and urine) have been described [table III]. The most sensitive and specific method seems to be the one described by Lindstrom et al. (J 975). In this method, hydrochlorothiazide is subjected to an

Fig. 2. Structural formula of hydrochlorothiazide.

Clinical Pharmacokinetics of Diuretics

224

extractive alkylation where tetramethylhydrochlorothiazide is formed. III Bioal'ailability The uptake of hydrochlorothiazide at different levels of the gastrointestinal tract was studied in healthy subjects who received a test solution containing 14C-hydrochlorothiazide and a non-absorbable marker. Uptake was estimated by comparing the ratio between concentration of radioactivity and marker in a series of aspirates with that in the test solution. Absorption took place primarily in the duodenum and the upper jejunum. Since 95 % of a dose of hydrochlorothiazide is eliminated in unchanged form via the kidneys, the total amount of the

drug absorbed should therefore be close to the amount of hydrochlorothiazide eliminated in the urine (Beermann et aI., I 976b). The uptake of hydrochlorothiazide in fasting healthy subjects averaged 65 % and was not dose-dependent over the dose range 5 to 75mg of hydrochlorothiazide (Beermann and Groschinsky-Grind, 1977). The gastrointestinal absorption of hydrochlorothiazide was increased to about 75 % when it was given concomitantly with food (Beermann and Groschinsky-Grind, 1978a). Pretreatment with 60mg of propantheline increased the amount of a dose absorbed to approximately 90 %, suggesting that decreased gastric emptying rate enhanced the uptake (Beermann and Groschinsky-Grind, 1978b).

Table II. Pharmacokinetic data of hydrochlorothiazide after oral administration

Reference b

Subjects· (n)

Dose c (mg)

Bioavailability (urinary recovery; %)

Renal clearance (ml/min)

Beermann and Groschinsky-Grind (1977)

N (8)

12.5 Sd 25 50 75

68± 72± 65± 65±

345± 123 332± 139 340± 121 319±86

16 17 17 10

Beermann and Groschinsky-Grind (1978a)

NF(8)

75Sd

74± 7

Beermann and Groschinsky-Grind (1978b)

NP(6)

75Sd

89±6

Beermann and Groschinsky-Grind (1978c)

HT(9)

75Md

59± 10

Beermann and Groschinsky-Grind (1979)

CF (7)

50, 75Sd

43 ± 18 d

Backman et al. (1979)

IS(5)

a

b c d

9.5 ± 3.6d (n=8)

317±120 19.1± 7.3 (n = 6)d

75mg Sd

31 ± 4.4

Normal. fasting N Normal, with food NF Normal, pretreated with propantheline NP Hypertension HT CF Cardiac failure IS Intestinal shunt. Concentrations of hydrochlorothiazide were determined with gas liquid chromatography. Md =- Multiple dosing Sd = Single dose. Recalculated from author's data.

73± 59 d

225

Clinical Pharmacokinetics of Diuretics

Table /II. Methods for determination of hydrochlorothiazide in plasma and urine

Reference

Method"

Sensitivity

Biological fluid analysed

Sheppard et al. (1960)

Spectrophotometry

lO)lg/ml

Urine

Lindstrom et al. (1975)

GLC

10ng/ml

Plasma, erythrocytes, urine

Vandenheuvel et al. (1975)

GLC

50ng/ml

Plasma, urine

Cooper et al. (1976)

HPLC

50ng/ml .

Plasma, urine

Solberg-Christophersen et al. (1977)

HPLC

50ng/ml

Plasma, urine

a

GLC HPLC

= Gas liquid chromatography. = High performance liquid chromatography.

Cook et aJ. (J 966) and McGilveray et aJ. (J 973) found great differences in dissolution rate from several commercial preparations of hydrochlorothiazide. The bioavailability did not correlate with the dissolution rate in vitro (Corrigan et a!., 1976; McGilveray et aI., 1973). Meyer et a!. (J 975) studied the bioavailability in vivo of 7 different hydrochlorothiazide preparations and no difference was found between them. Similarly, Beermann et a!. (J 977c)found no difference in the bioavailability of 2 different hydrochlorothiazide preparations. 1.2.2 Binding to Blood Elements Hydrochlorothiazide accumulates in erythrocytes by an unknown mechanism. The ratio between blood corpuscles and plasma is 3.5: 1 (Beermann et a!., I 976b). The protein binding of hydrochlorothiazide is approximately 40% (unpublished observations). 1.2.3 Plasma Kinetics Cooper et a!. (1976) gave 5 healthy men an oral dose of hydrochlorothiazide of 1mg/kg. Blood samples were taken 6 to 10h after intake of the drug. The analyses of hydrochlorothiazide were made by high pressure liquid chromatography. The half-life of hydrochlorothiazide was calculated by a dator technique according to a I-compartment open model and averaged 5.2h (mean value). However, the decline in

the plasma concentration of hydrochlorothiazide was found to be biphasic when followed for at least 24h. The half-life of the slower phase ranged from 5.6 to 14.8h and appeared at 8 to 10h after the administration of hydrochlorothiazide. Maximum plasma levels after 12.5, 25, 50 and 75mg hydrochlorothiazide (administered orally) were seen at 1.5 to 5h and averaged 70,142,260 and 376ng'ml- 1 respectively. The peak plasma levels and the area under the plasma concentration-time curve increased proportionally with dose indicating non dose-dependent kinetics (Beermann and Groschinsky-Grind, 1977). The apparent volume of distribution can be estimated to be about 3L1kg (unpublished data). 1.2.4 Elimination Chromatographic separation of the labelled compounds present in urine from subjects given 14C_ hydrochlorothiazide orally, showed that more than 95 % hydrochlorothiazide is excreted in unchanged form via the kidneys (Beermann et al., 1976b). The remll clearance of hydrochlorotpiazide was approximately 335ml/min after 12.5 to 75mg hydrochlorothiazide was given to subjects with normal renal function (Beermann and Groschinsky-Grind, 1977). The high renal clearance indicates tubUlar secretion. A small percentage of 14C-hydrochlorothiazide, administered intravenously, was excreted with

Clinical Pharmacokinetics of Diuretics

226

the faeces which indicates a secretion of the drug from the gut as no excretion could be traced from the gall bladder (Beermann et aI., I 976a). J.2.5 Kinetics in Disease States Congestive heart failure: When hydrochlorothiazide was given orally to patients suffering from congestive heart failure great differences in absorption were found. Absorption ranged from 20 to 70%, measured as urinary recovery of hydrochlorothiazide during 7 days. The half-life of hydrochlorothiazide was increased up to 28. 9h. Renal clearance of hydrochlorothiazide varied from 10 to I 87ml/min and it was correlated with the endogenous creatinine clearance (Beermann and Groschinsky-Grind, 1979). Patients with intestinal shunts: The absorption of hydrochlorothiazide was diminished to about 30 % in patients who had undergone intestinal shunt. operation for obesity. This can be explained by rapid intestinal transit as in some of these patients the passage through the gut from mouth to caecum took only 2 minutes. The area under the plasma concentrationtime curve (AUe) was only 50 % of that in healthy volunteers (Backmann et al., 1979).

J .2.6 Relationship between Plasma Levels and Effects

Maximal diuresis and natriuresis were found after 12.5mg of hydrochlorothiazide was given orally to healthy fasting subjects. There was no correlation between the area under the plasma concentration-time curve and the diuresis or the excretion of electrolytes (Beermann and Groschinsky-Grind, 1978c). The antihypertensive effect of hydrochlorothiazide was not related to the plasma levels of the dnig in 9 hypertensive patients treated with 12.5, 25. 50 and 75mg hydrochlorothiazide over a period of 2 weeks (Beermann and Groschinsky-Grind, 1978c). 1.3 Hydroflumethiazide (table IV) Hydroflumethiazide (fig. 3) is a thiazide with approximately the same potency as hydrochlorothiazide.

Fig. 3. Structural formula of hydroflumethiazide.

For determination of hydroflumethiazide, Br0rs et al. (1977) developed a spectrofluorometric assay. J.3. J Bioal'ailability

There are no data on the absolute bioavaiIability of hydroflumethiazide. The urinary recovery of unchanged drug after oral administration indicates a minimal bioavailabiIity of about 50 % (Br0rs et aI., 1978; Yakatan et al.. 1977). Studies by McNamara et al. (] 978) suggest that the gastrointestinal uptake of hydroflumethiazide is best described by zero-order absorption. J.3.2 Binding to Blood Elemell/S

The binding of hydroflumethiazide to albumin is about 95 % (Agren and Back, 1973). Bmrs et al. (1977) found that the mean blood:plasma concentration ratio of hydroflumethiazide was 1.74:2. 30h after administration of the drug. This indicates some binding of the drug to blood cells. J.3.3 Plasma Kinetics

Bf0rs et al. (1977) and Yakatan et al. (]977) reported that the plasma levels of hydroflumethiazide declined monoexponentially with a tl /2 of about 2h. However, they based their conclusion on the plasma concentration-time curve over a period of only 12h. Bf0rs et al. (1978) analysed the urinary excretion rate for 48 to 85h after oral administration of 100mg hydroflumethiazide and found a biexponential pattern. The tll2a averaged 1.91h and t1l2~ 16.6h. The lack of information on the degree of gastrointestinal uptake invalidated calculations of apparent volume of distribution and plasma clearance.

227

Clinical Pharmacokinetics of Diuretics

Table IV. Pharmacokinetic data of hydroflumethiazide after oral administration of l00mg

Reference

Subjects·

Half-fife (h)

(n)

Bmrs et al. (1978)

a b c

Renal clearance (ml/h/kg)

Assayb

SFM, SFD

a phase

~

N (5)

1.9±0.5e

16.6 ± 6e

0.32-0.34 (n=2)

CF(9)

2.2 ± O.4 e

9.6± 2.8 e

0.21 ±0.07 e

phase

N Normal CF Cardiac failure. SFM = Spectrofluorometry SFD = Spectrofluorometry of TLC plates: Recalculated from author's data.

1.3.4 Elimination Hydroflumethiazide is in part eliminated unchanged via the kidneys; the renal clearance averaging 0.32 to 0.34L1h/kg and 453 ± 256ml/min according to Bfl'Jrs et al. (J 978) and Yakatan et a!. (1977) respectively. About 2 % of an orally administered dose of the diuretic is eliminated via the kidneys as the metabolite 2,4-disulphamyl-trifluormethylaniline (Bf0rs et a!., 1978).

A sensitive GLC assay of polythiazide has been described by Hobbs and Twomey (1978).

1.4. I Bioavailability and Binding to Blood Eleme(1ts No data are available on bioavailability. Polythiazide is 83.5 % bound to plasma proteins (Hobbs and Twomey, 1978).

1.4.2 Plasma Kinetics and Elimination 1.3.5 Pharmacokinetics in Cardiac Failure The average urinary recovery of the drug after oral administration to patients with cardiac failure is similar to that in healthy subjects, indicating unchanged gastrointestinal uptake. The tl /2a and tl /2~ averaged 2.12h and 9.6h respectively. The renal clearance (0.21 Llh/kg) was lower than in healthy subjects (Brers et a!., 1978). The shortening of the elimination half-life, despite decreased renal elimination, might be explained by decreased apparent volume of distribution in cardiac failure.

After a single oral dose of 1mg of polythiazide in healthy fasting volunteers, the peak level was seen at 5h (mean value) and varied from 2.0 to 7.4ng/ml. The average half-life was 25. 7h (Hobbs and Twomey, 1978). In healthy subjects the total urinary recovery of unchanged polythiazide after 48h is 20 % following a

I .4 Polythiazide Polythiazide (fig. 4) is one of the most potent thiazides and is normally used in doses of I to 4mg.

Fig. 4. Structural formula of poly thiazide.

228

Clinical Pharmacokinetics of Diuretics

single oral dose of I mg of polythiazide. There are no data available which concern metabolism of the drug (Hobbs and Twomey, 1978).

to plasma proteins at therapeutic concentrations averaged about 75% (Col\ste et al.. 1976; Dieterle et al.. 1976). The major binding protein was albumin. to which 689G of chlorthalidone was bound. Albumin had 4 binding sites and the association constant 1.5 Chlorthalidone(table V) was 1.18· IOJUmole(Dieterieetal.. 1976). Tweeddale and Ogilvie (1974) reported that Chlorthalidone is a diuretic with pharmacological human blood cells contained much higher levels of effects similar to thiazides, although it differs chlorthalidone than plasma. This was verified by chemically from that group (fig. 5). It has a potency Beermann et al. (l975b). who found that the consimilar to that of hydrochlorothiazide. centration of chlorthalidone was 50 to 80 times highFor determination of chlorthalidone in biological er in blood cells than in plasma after a single dose of fluids, Ervik and Gustavii (\ 974) developed a GLC 25mg. Similar ratios have been shown by several assay based upon extractive alkylation. The assay has authors (Collste et aI., 1976; Fleuren and van been modified (Riess et aI., 1977; FIeuren and van Rossum. 1975; Riess et al.. 1976). At steady-state Rossum, 1978; Mulley et al., 1978). during treatment with SOmg daily. only 1.4 % of the total amount of chlorthalidone in whole blood was found in plasma. Several lines of evidence indicate 1.5.1 Bioal'ailability The bioavailability of chlorthalidone was studied that the binding is caused by high affinity of by FIeuren et al. (1979). 7 volunteers were given chlorthalidoneto erythrocyte carbonic anhydrase. SOmg chlorthalidone orally and by infusion over a For example. the strong carbonic anhydrase inhibitor period of 2 hours. The bioavailability was estimated acetazolamide displaced chlorthalidone in vitro and in by comparing the plasma levels and urinary excretion vivo from erythrocytes (Beermann et al.. 1975b). The of the drug respectively following the 2 routes of ad- high affinity to carbonic anhydrase wa.<; demonstrated ministration and it averaged 64 %. The mean absorp- by Dieterle et al. (1976). The association constants for tion rate constant was 31 minutes. Riess et al. (1977) erythrocyte carbonic anhydrase isoenzyme Band C gave 50, 100 and 200mg of the diuretic orally to 6 . were 2.43 . I06Umoie and 5.69 . 106Umoie reshealthy volunteers. The absorption half-life was pectively. Both isoenzymes possessed I binding site about 2.6h which disagrees with the results of per molecule. The uptake of chlorthalidone in eryFleuren et al. (\ 979). The earlier study group, how- throcytes is saturable and the saturation seems to oceVer, based their caiculations on blood concentrations cur at whole blood concentrations of 15 to 20fJg/ml which is not relevant in view of the high binding of (Collste et al.. 1976; Dieterle et al.. 1976). chlorthalidone to erythrocytes. The relative urinary recovery of chlorthalidone was significantly lower after a 200mg dose than after a 50mg dose, suggesting dose-dependent bioavailability. This suggestion was supported by the finding that the ratio between AUC o _ 00 after 50 and 200mg was 1:3.1 and not 1:4 as expected. 1.5.2 Binding to Blood Elements

A very small fraction of chlorthalidone in blood is unbound. This is due to both protein binding and the extensive accumulation in erythrocytes. The binding

Fig. 5. Structural formula of chlorthalidone.

m

(10)

(5)

50 Sd iv 50Sdpo

64-13

Bioavailability (%)

l00-2ooSdpo

50Sd po 100 Sd po 200 Sd po 50 Md po

5OSdpo

00se 8 (mgl

75.7±0.2 (± SEI

74.8± 1.2

Protein binding (%)

98.5

98-99

95

Erythrocyte binding (%1

a Sd = single dose; Md = multiple dosing. b All assays of chlorthalidone were performed by gas liquid chromatography. c 'Recalculated from author's data.

Flauren et al. (1979)

Aeuren and van Rossum (1977)

Riess et al. (1977)

(5)

(5) (41

CoIlste et al. (1975)

Dieterle et al. (1975)

Subjects (nl

Reference b

60±8

erythrocytes

44.1± 9.6c 52.7 ± 9.0c (po)

(po)

40±8

49.0±9.S 46.9± 13.0 41.8±5.1 49±5.1

S4.8± 11.2

plasma

tl/2~ (h)

Table V. Pharmacokinetic data of chlorthalidone in healthy subjects (mean ± 501

292± 20C (ivl

(L1

Vd ss

59.6± 8.8

III ±2OC 69± l1 C (iv) (ivl

93±41

systemic renal

Clearance (ml/minl

42± 12 (iv)

non-renal

'"<0'"

Cil

Ig'

2'

o

IS-~.

II.

3

~

~

Q

:i" ,i"

Clinical Pharmacokinetics of Diuretics

1.5.3 Plasma and Erythrocyte Kinetics The plasma kinetics of chlorthalidone after a single oral dose fit an open 2-compartment model (Fleuren and van Rossum, 1977). The apparent volume of distribution at steady-state averages 292L (Fleuren et a!., 1979). The mean half-life of the terminal phase of the plasma concentration-time curve after 50 to 200mg, given orally, was 40h (Fleuren and van Rossum, 1977, 1978). This agrees well with the half-lives of chlorthalidone determined by renal elimination rate curves (Riess et aI., 197?). A longer plasma half-life (65h) was found in one study (Collste et al., 1976). The elimination rate did not appear to change during long term treatment (Riess et al., 1977). The uptake and elimination of chlorthalidone in erythrocytes fits an open I-compartment model with first-order absorption. The elimination half-life is 53h after 50mg orally (Fleuren et aI., 1979). A somewhat longer elimination half-life (60h) was found after 100 and 200mg (Fleuren and van Rossum, 1977). The difference in elimination rate of chlorthalidone from plasma and erythrocytes can be explained by a pharmacokinetic model which includes non-linear binding of the drug to erythrocytes (Fleuren and van Rossum, 1977). 1.5.4 Elimination The major part of an absorbed dose of chlorthalidone is excreted unchanged via the kidneys (Beermann et ai., i 975b; Coiiste et aI.. i 976; Riess et aJ.. 1977; Fleuren et aI., 1979). Plasma clearance after intravenous administration of chlorthalidone averaged III ml/min and mean renal and non-renal clearance was 69 and 42ml/min, respectively [recalculated from Fleuren et al. (1979)]. Similar renal clearance (60mll min) was found by Riess et a!. (J 977). A somewhat lower plasma clearance (93ml/min), was found in I study (Collste et aI., 1976), which can be explained by underestimation of the bioavailability of chlorthalidone. The non-renal routes of elimination have yet to be clarified. After oral administration of 14C-chlorthalidone, about 10% of the urinary radioactivity

230

showed chromatographic properties other than those of chlorthalidone, suggesting some metabolism of chlorthalidone (Beermann et al. ! 975b). After intravenous administration, about I to 9 % of the dose is recovered unchanged in the faeces, demonstrating biliary or intestinal elimination of the drug (Fleuren et a!., 1979). Placental and milk tran~rer: Babies born to mothers treated with 50mg chlorthalidone daily had at delivery blood concentrations of chlorthalidone which were 5 to 16 % of the maternal blood level. Three days after delivery the concentration in maternal milk ranged between 0.09 and O.86)Jg/ml (Mulley et aI., 1978).

2. Loop Diuretics 2.1 Frusemide (furosemide) Frusemide (fig. 6) in contrast to the thiazides is effective in renal failure. Clinically used doses range from 20 to 3000mg. The clinical pharmacokinetics of frusemide have been reviewed in detail in a previous issue of the journal (Cutler and Blair, 1979). 2.1.1 Assays of Frusemide The kinetics of frusemide have been studied with different assays. In some studies, plasma levels of frusemide were determined with spectrofluorometry according to Hajdu and Haussler (1964) with modifications (Huang et a!., 1974). The assay used by Cutler et al. (1974) and Kelly et al. (1974) was sensitive to

Fig. 6. Structural formula of frusemide (furosemide).

231

Clinical Pharmacokinetics of Diuretics

0.5)Jg/ml changes in serum. The lowest plasma concentration of frusemide used for preparation of standard curves in the study of Homeida et al. (1977) was 0.5)Jg/ml (Branch et aI., 1977). It has been shown that the spectrofluorometric assay is unspecific and insensitive, especially in patients taking other drugs and in patients with renal disease (Andreasen et aI., 1978a; Mikkelsen and Andreasen, 1977). This lack of sensitivity and specificity is important as plasma levels- of frusemide after normal doses of the drug very soon decline to under 1)Jg/ml. The spectrofluorometric assay was improved substantially when a chromatographic procedure was included (Mikkelsen and Andreasen, 1977). Honari et al. (I977) and Tilstone and Fine (t 978) based their pharmacokinetic analysis on plasma and urinary concentration of radioactivity after administration of J5S-frusemide. Blair et al. (I 975), however, showed that radiochemical determination overestimated the concentration of frusemide by 200 to 300 %, 2 to 3 hours after injection of J5S-frusemide to healthy subjects. Specific assays of frusemide other than that of Mikkelsen and Andreasen (I 977) include GLC (lindstrom, 1974) and HPLC (Blair et aI., 1975; Carr et al., 1978; Lindstrom and Molander, 1974). 2. J.2 Bioavailability (table VI) The gastrointestinal uptake of frusemide has been estimated by comparisons of the plasma levels and/ or urinary excretion of unchanged frusemide or radioactivity after oral and intravenous administration of the drug. Most authors conclude that approximately 65 % of an oral dose of frusemide is absorbed (Beermann et a\., 1975a; Rane et al., 1978; Rupp, 1974; Tilstone and Fine, 1978) although some have found a somewhat smaller uptake (Branch et al., 1977; Kelly et al., 1973). Kelly et al. (1974) administered frusemide with and without food and found that the postprandial uptake was delayed. It is uncertain whether it also was quantitatively changed as the assay of frusemide in plasma was insensitive. The bioavailability of 2 commercial brands of frusemide tablets was identical in a single dose study (Beermann et aL 1978a).

Table VI. Bioavailability of frusemide Reference

Subjects (n)

Bioavailability (%)

Beermann et al. (1975a)

Normal (7)

67

Branch et al. (1977)

Normal (6)

52

Heart failure (7)

61 (34-79)

Kelly et al. (1974)

Normal (8)

50

Rane et al. (1978)

Normal (6) Uraemia (6) Nephrosis (6)

63±9 46±9 46±9

Rupp (1974)

Normal (5)

68

Tilstone and Fine (1978)

Normal (5) Uraemia (6)

69± 7 43± 7

Greither et al. (1976)

2. J.3 Bil/dil/g 10 Blood Elements (table VII) Frusemide is extensively bound to plasma proteins, mainly to albumin (Prandota and Pruitt. 1975). The unbound fraction averages 2.3 to 4.1 % at therapeutic concentrations (Andreasen and Mikkelsen. 1977; Andreasen et al., 1978b; Prandota and Pruitt. 1975; Rane et al.. 1978) and is unchanged up to concentrations of I OOllg / ml. which is higher than that after normal therapeutic doses (Rane et al., 1978). 2. J.4 Plasma Kil/etics (table VJI) There is general agreement that the kinetics of frusemide are best described by an open 2-compartment model. When the plasma levels of frusemide were determined with specific methods. the half-life of the a phase averaged 10 to II minutes (Mikkelsen and Andreasen. 1977; Rane·et al., 1978) and that of the ~ phase 47 to 57 minutes (Beer mann et al., I 977a; Mikkelsen and Andreasen. 1977; Rane et al.. 1978).

72±26

P(4)

Riva et al. (1978)

15.0+3.6e

17.1 ±3.8

14.1 ± 3.3 e

(l)

110+ 7 124+9 182± 27

265± 152

174±30 197 ± 33

(ml!kg)

Vd ••

219±49 66± 19

(ml/min)

13.8±6.2

152± 23

208± 34

194± 35

18.7± 12.6 130± 73

13.1±1.7 10.0±0.2

(Ll

systemic

Clearance

1.8± OAe

2.2+0.1 0.6±0.1 2.9±0.5

2.9 + 0.4c

1.3 + 0.3

1.8± 1.9

3.0± 0.7 1.3± 0.4

(ml/min/kg)

104 ± 0.7 e

1.0 ± O.~:e

1.1 ±0.1 1.1±0.2 0.06± 0.01 0.6± 0.1 1.2 ± 0.3 1.8± 0.4

lA± 0.4e

0.8±0.6e

renal non-renal (ml/min/kg) (ml/min/kg)

a N = Normal; U = Uraemia; HT = Hypertension; NB = Newbom; NEP = Nephrosis; P = Pregnancy. b FTlC = Fluorimetry and thin layer chromato~lraphy; GlC· = Gas liquid chromatography; HPlC = High performance liquid chromatography. c Recalculated from author·s data.

51 ±4 156±85 54±6

N(6) 4.1 ±0.1 U(6) 5.6±0.5 NEP (6)6.8 ± 0.5

Rane et al. (1978) 180± 20

N(5)

Beermann et al. (1971a)

57

21O± 56

52 ± 15e

·NB(8)

Aranda et al. (1978)

N(12) Mikkelsen and Andreasen I 1971)

829± 119

462±60e

N (7) 2.3±0.3 HT (7) 2.9 ± 0.8 e

(ml/kg)

Vd~

Volume of distribution

Andreasen et al.11978b)

3.3±OA

(min)

t1/2~

N(7) U(7)

(%)

Subj.a Unbound (n) frusemide

Andreasen et al. (1978a)

Reference

Table VII. Pharmacokinetic data of frusemide after intravenous administration. Studies where specific assays were used are included

GlC

HPlC

FTlC

GlC HPlC

GlC

FTlC

FTlC

Assayb

Q

IV W IV

.,

S cr

c:

9-

S.

.,cr

~

:::l

n 0 2r.

Q)

3'"

~

'l!..

cr

:r

233

Clinical Pharmacokinetics of Diuretics

V d~ ranges from 14.1 to 17. I L (mean value) [Heermann et a!., 1977a; Mikkelsen and AndreaSen, 1977]. Apparent volume of distribution at steadystate (VdsJ averages 13.1 to 13.8L, which corresponds to approximately 190ml/kg (Andreasen et a!., 1978a; Mikkelsen and Andreasen, 1977). Rane et a!. (1978) found a somewhat lower mean value for V d&~ of II Oml/kg. 2.1.5 Elimination (table VII) The plasma clearance of frusemide is approximately 2.2 to 3.0mIlmin/kg (Andreasen et al., 1978a; Heermann et al., 1977a; Mikkelsen and Andreasen. 1977; Rane et a!.. 1978). Renal excretion of unchanged drug (mainly via tubular secretion) and non-renal elimination contribute almost equally to the plasma clearance. but there is considerable interindividual variability in both pathways (Beermann et al., I 977a; Rane et al., 1978). Glomerular filtration appears to be of small importance in view of the high binding of this drug. Frusemide is in part eliminated via the kidneys as metabolite(s). Hajdu and Haussler (J 964) and Haussler and Wicha (1965) reported that 2-amino-4chloro-5-sulphamoylanthranilic acid (CSA) was the only metabolite in man. Several other authors (Andreasen and Mikkelsen. 1977; Heermann et aJ., 1975a; Carr et aJ.. 1978; Kindt and Schmid, 1970) found no evidence for the existence of this compound in urine or plasma while still others confirmed its existence (Andreasen et aJ.. I 978a). Frusemide degrades spontaneously to CSA in Fitm when exposed to light, which might explain the controversy about the existence of this metabolite. There is better agreement that frusemide is, to some extent, excreted via the kidneys as a glucuronide (Andreasen and Mikkelsen, 1977; Beermann et a!., 1975a; Carr et a!.. 1978) which most likely is inactive. After intravenous administration of 35S-frusemide. about I 0 % of the radioactivity is recovered in the faeces (Beermann et al.. 1975a; Rupp, 1974). Some of that radioactivity seems to be excreted into the intestine via the bile (Heermann et al.. 197 5a, I 977a).

2.1.6 Kinetics in Pathophysiological States (table VII) Renal diseases: The oral bioavailability was decreased about 33 to 45 % in patients with advanced renal failure and in those with nephrosis (Rane et aI., 1978; Tilstone and Fine, 1978). Binding of frusemide to plasma proteins was decreased in proportion to the reduction in albumin concentrations (Prandata and Pruitt. 1975; Rane et aJ., 1978). The apparent volume of distribution was increased in proportion to the fraction of unbound frusemide (Andreasen et al.. I 978a; Rane et al., 1978). The mean plasma half-life of frusemide in patients with nephrosis did not differ from that in normal subjects but was prolonged about 3-fold in patients with uraemia (Rane et aI., 1978). There appears to be great interindividual differences in plasma half-life in patients with similar degrees of renal failure. 2 patients with creatinine clearance about 5ml / min had plasma half-lives of 1.55 and 24.58h respectively (Heermann et aJ.. I 977a). The systemic clearance of frusemide correlated negatively with creatinine clearance. This could be attributed to both decreased renal and non-renal elimination (Andreasen et al., 1978a; Beermann et a!., I 977a; Rane et a!.. 1978). Arterial hypertension: Patients with severe hypertension and various degrees of impaired renal function had a significantly lower systemic plasma clearance (130ml/min), than normal subjects (219mJ/ min). Hoth systemic and renal clearance of frusemide were inversely correlated with mean blood pressure. Vdss and plasma protein binding did not differ from that in normal subjects. A highly significant negative correlation was found between systemic clearance of frusemide and the fraction of frusemide excreted as a glucuronide (Andreasen et aI., I 978b). Heart failllre: Gastrointestinal uptake of frusemide in patients with heart failure appears to be of the same magnitude as in normal subjects (Greither et aI., 1976). The apparent volume of distribution did not change in patients with heart failure, but systemic clearance was lower in patients not previously treated with frusemide (83.5 ± 15.9mJ/min) than in con-

Clinical Pharmacokinetics of Diuretics

trois (t 6S.9 ± 42.4ml/min). Whether the decrease in systemic clearance was due to impaired renal function cannot be judged from the data presented by Andreasen and Mikkelsen (J 977). Pregnancy: Riva et al. (t 978) administered intravenous frusemide to pregnant women with oedema and/or hypertension. No controls were included in the study. Compared with data from other studies, pharmacokinetic parameters did not appear to be changed in these patients. In 2 cases, concentrations of frusemide were determined in umbilical vein plasma and it was somewhat lower than in maternal plasma. Placental transfer of frusemide was also shown in a study where I 8 women were given frusemide orally at delivery. There was a linear relationship between time after intake of frusemide and the ratio between its concentrations in umbilical cord vein plasma and in maternal vein plasma. At 8 to 10h, the concentration of frusemide in umbilical cord vein plasma was the same as in the mother's plasma. The concentration of the diuretic in amniotic fluid was in most cases lower than that in umbilical cord vein plasma (Beermann et aI., I 978b). Neonates: Aranda et al. (t 978) administered I to I Smg frusemide intravenously to newborn children with fluid overload. Their gestational and postnatal age averaged 35.0 ± 1.8 weeks and 11.5 ± S.9 days respectively. The apparent volume of distribution (V d area) was 829ml/kg (mean value), which is about 4 times higher th~'1 that in adults. The plasma clearance was approximately half of that in adults (t .3mllkg/ min), resulting in a substantially prolonged half-life of frusemide, which averaged 462min. The administration of frusemide did not change bilirubin binding capacity.

2.1.7 Relationship between Pharmacokinetics and Clinical Effects Frusemide is in part cleared via the kidneys, mainly via tubular secretion. By blocking tubular secretion with probenecid it has been shown that the renal effects of the diuretic are dependent on the luminal tubular concentration of the drug (Brater,

234

1978; Homeida et ai., 1977; Honari et aI., 1977; Odlind and Beermann, 1978). When frusemide was infused intravenously to S subjects at a rate of 8mg/h, the diuresis averaged about I Oml/min. After injection of I g probenecid intravenously, urinary excretion of frusemide decreased and plasma levels of frusemide increased. The diuresis decreased to about Smllmin. There was no or a negative correlation between plasma levels of frusemide and diuresis and urinary excretion of sodium, potassium and chloride. However, urinary output of frusemide was highly correlated with the various renal effects (Odlind and Beermann, 1978). Plasma levels of frusemide exceeding SOJ.lg/ ml are associated with a high frequency of hearing disturbances (Wigand and Heidland, 1971). Such levels are seen in azotaemic patients administered 2 to 3g frusemide orally (Beermann et aI., 1977a).

2.2 Bumetanide(table VIII) Bumetanide, a metanidamide derivative (fig. 7), has pharmacological actions similar to frusemide (furosemide) although its relative potency is approximately 40 times greater.

2.2.1 Assay o.f Bumetanide The plasma levels of this diuretic have been measured as total plasma radioactivity (Davies et aI., 1974) and as elher (Pentikainen et ai., 1977) or benzene extractable radioactivity (Halladay et aI., 1977) after administration of 14C-bumetanide. The

H2N-S02~ COOH

O'\oY -

NH-CH 2-CH 2-CH 2-CH 3

Fig. 7. Structural formula of bumetanide.

235

Clinical Pharmacokinetics of Diuretics

Table VIII. Pharmacokinetic data of bumetanide in healthy subjects

Reference

Subjects (n)

Bioavailability

t'/2~ (h)

(%)

Davies et al.

Assay·

Volume of distribution

Clearance (ml/min)

(Ll

systemic

renal

non-renal

2

0.3

12.3-12.5

194-209

96-107

9S-102

GLC

Dixon et al. (means ± SE)

S

1.2±0.1

35.2 ± 3.7 b

255± 26

107± 11

14S± 19b

RIA

Halladay et al.

3

1.3 ( 1.2-1.4)

24.5 (15.S-39.1I

220 (131-375)b

126 (SO-195)b

101 (51-1S0)b

14C

(1974)

(1977) Pentikainen et al. ( 1977) a b

4

96

l·C

1.5±0.2

GLC = Gas liquid chromatography; RIA = Radioimmunoassay; '4C = Extractable radioactivity. Recalculated from author's data.

authors state that only bumetanide is recovered in the organic phase after extraction. The concentrations have also been assayed with GlC (Feit et aI., 1973; Davies et aI., 1974) and with radioimmunoassay (Dixon et a\., 1976). 2.2.2 Bioavailability

Halladay et al. (1977) administered 2mg 14C_ bumetanide orally to 4 volunteers. The urinary recovery of radioactivity ranged from 76.8 to 8 S.4 % of the given dose. Bile was collected for 24 hours in the subject with the. lowest urinary recovery. It contained 14.4 % of given radioactivity which indicates an oral bioavailability of at least 90 %. The concept of an almost complete bioavailability of bumetanide is supported by the findings of Pentikainen et al. (1977). They found that the ratio between the recovery of radioactivity after oral and intravenous administration of 14C-bumetanide to 4 healthy volunteers averaged 0.96. The absorption of radioactivity followed first-order kinetics with an absorption halflife of 0.61 to 0.007h. 2.2.3 Binding (0 Blood Elements

The protein-bound fraction of bumetanide in plasma was 96 ± 1 % measured with ultrafiltration.

There appears to be no binding to erythrocytes (Pentikainen et al., 1977). 2.2.4 Plasma Kinetics

Various assays of bumetanide, scattered or short sampling of plasma and very low plasma levels, makes it difficult to obtain a clear understanding of the plasma kinetics of the drug. The decline of the plasma concentration has been described as both monoexponential (Davies et aI., 1974; Pentikainen et aI., 1977) and biexponential (Halladay et aI., 1977). Accordingly, the values for apparent volume of distribution differ markedly, from about 12l (Davies et aI., 1974) to 3SL (Dixon et al., 1976) in healthy subjects. There is better agreement about the half-life of the terminal phase of the plasma concentration-time curve which averages 1.2 (Dixon et aI., 1976) to I.Sh (Halladay et al., 1977; Pentikainen et al., 1977). Davies et al. (1974), however, found a substantially shorter half-life (about 0.3h), which might be explained by the observation time being too short. 2.2.5 Elimination

Bumetanide is cleared from plasma at an average rate of 200 to 2S0ml/min. Elimination via the kid-

I

I

" S-CO-CH 3

+--o

I

Canrenone

o

o

I

I Canrenoic acid

Potassium canrenoate

Fig. 9. Initial steps in metabolism of spironolactone and potassium-canrenoate (after Abshagen et al.. 1976\.

o

o

Spironolactone

:r

Q

0>

'" W

S .~'

2 c:

s..

S rr en

:::I

z;:

o

.,~ .,n3

!!!.

rr

237

Clinical Pharmacokinetics of Diuretics

neys constitutes about half that clearance (Davies et aI., 1974; Dixon et aI., 1976; Halladay et aI., 1977). After administration of 14C-Iabelled bumetanide, 10 to 20 % of the radioactivity was recovered in the faeces (Halladay et aI., 1977; Pentikainen et al.. 1977) mainly in form of alcohols (Halladay et aI., 1977). Data from 1 patient indicated that most of that radioactivity had been secreted to the gut via the biliary tract. Small amounts of unmetabolised drug in bile contradicted any important enterohepatic circulation (Halladay et a1., 1977). The principal metabolites in urine were conjugated alcohols of bumetanide (Halladayet al.. 1977; Pentikainen et aI., 1977).

2.2.6 Pharmacokinetics in Renal Failure In renal failure, only a small percentage of bumetanide is recovered in urine. The plasma half-life of the drug has not been determined accurately but did not appear to be longer than in healthy controls (Barclay and Lee, 1975; Berg et aI., 1976).

3. Potassium Sparing Diuretics 3.1 Amiloride Amiloride (fig. 8) is a potassium retaining diuretic, although it does not act as an aldosterone antagonist. Schmid and Fricke (I 969) have developed a spectrofluorometric assay of amiloride.

3.1.1 Bioal'ailability Amiloride is excreted via the kidneys in unchanged form (Weiss et aI., 1969). It is not known whether the drug is also excreted into the gut. The urinary output of the diuretic thus represents the minimum gastrointestinal absorption. Weiss et al. (I969) recovered 52 ± 5 % of the radioactivity in urine collected for 96h after 20mg 14C-amiloride orally to fasting subjects. After administration of 10 to 20mg unlabelled amiloride to fasting subjects, 61 % of the dose was found in the urine after 48h (Schmid and Fricke, 1969). The recovery was signifi-

Fig. 8. Structural formula of amiloride.

cantly lower (3 1 %) when the drug was given with food, indicating decreased absorption. Amiloride is often given combined with hydrochlorothiazide in fixed dose pharmaceutical preparations. The uptake of the thiazide is increased (Beermann and Groschinsky-Grind, 1978a) when taken with food in contrast to that of anliloride. The divergent effects of food on the absorption ofthe fixed dose combination indicate that it should be taken on an empty stomach.

3.1.2 Plasma Kinetics and Elimination The half-life of amiloride in plasma (determined as radioactivity after oral administration of 14C-amiloride) averages 9.6 ± 5.lh (Smith and Smith, 1973). Apparent volume of distribution was estimated to be 350 to 380L when the urinary recovery of radioactivity was assumed to represent the total bioavailability. As previously stated, amiloride is excreted unchanged via the kidneys. The renal clearance was 523 ± 96ml/min in 5 subjects demonstrating tubular secretion of the drug (Weiss et ai., 1969).

3.2 Spironolactone and Potassium Canrenoate Spironolactone and potassium canrenoate are steroid derivatives which are indirect aldosterone antagonists. Potassium canrenoate can be regarded as the potassium salt of one spironolactone metabolite

Clinical Pharmacokinetics of Diuretics

(fig. 9). The 2 compounds are therefore discussed together. 3.2.1 Bioal'ailability Spironolactone: Spironolactone undergoes an enterohepatic circulation and an extensive first-pass metabolism. Furthermore. it cannot be given intravenously to humans. These properties have invalidated determinations of the gastrointestinal uptake and systemic bioavailability of the drug. Abshagen et al. (I 977a) administered JH-spironolactone orally to patients with bile drainage. The urinary and biliary recovery of radioactivity during 4 days averaged 54 and 16 % respectively. which indicates a minimal uptake of 70%. Unchanged spironolactone has been recovered in plasma in only I study. suggesting low systemic bioavailability of this compound (Abshagen et al.. 1976). Canrenone is·the major pharmacologically active metabolite of spironolactone. Most studies on the relative bioavailability of spironolactone are based on comparisons of the plasma levels of canrenone determined with spectrofluorometry. The relative bioavailability of spironolactone from commercial tablets could be improved 4 times by changed pharmaceutical manufacturing (Gantt et aJ.. 1962) and did not differ from that after administration of spironolactone in a solution (Karim et al.. 1976b). The improvement in absorption could be explained on the basis of a faster dissolution rate (Levy .1962; Clarke et al.. 1977). The area under the plasma concentration-time curve of canrenone was about 30 % greater when spironolactone tablets were given with food than when administered after fasting overnight (Melander et al.. 1977). Whether the higher levels of canrenone were caused by improved gastrointestinal uptake of spironolactone or increased metabolism to canrenone was not studied. Potassium canrenoate: Sadee et al. (1973) administered potassium canrenoate intravenously. and orally. The plasma levels of canrenoate and its meta-

238

bolite canrenone were almost identical after the 2 routes of administration. indicating complete absorption and systemic bioavailability of potassium canrenoate. 3.2.2 Binding to Blood Elements The binding to plasma proteins of spironolactone and canrenone averages 98 % at plasma levels of 550. and 71 Ong / ml respectively. The ratios between the concentrations of the 2 compounds in erythrocytes and in plasma were 0.22 and 0.13 respectively (Karim et al.. I 976a). 3.2.3 Metabolism Spironolactone: The metabolism of spironolactone is very extensive and complex (fig. 10). The initial steps appear to be an esterolysis of spironolactone to a thiol intermediate which is subsequently \1ydrolysed to canrenone or methylated to thiomethylspironolactone. Canrenone is in enzymatic equilibrium with canrenoate (Garret and Won. 1971) which is further conjugated with glucuronic acid. Canrenone may also be hydroxylated to 15a-hydroxycanrenone. Thiomethylspironolactone undergoes hydroxylation. sulphoxidation. peroxidation and probably. conjugation [see Karim (t 978) and Abshagen et al. (t 976) for details]. After oral administration of spironolactone about 80 % is converted to canrenone according to Sadee et al. (1973). The concentration of canrenoate in plasma was about a third of that of canrenone. However. fractionation of the radioactivity in plasma after JH_ spironolactone administered orally showed that 30 to 50.% was extractable with organic solvents. During the first 2h. JH-spironolactone was the most prominent . extractable labelled compound according to Abshagen et al. (J 976). Subsequently. canrenone dominated (Abshagen et al.. 1976; Karim et al.. 1975. 1976b). Significant amounts of 6~-hydroxy­ thiomethylcanrenone were also found (Karim et al.. 1975. I 976b). Canrenoate and unidentified metabolites were recovered in the non-extractable plasma fraction (Abshagcn et al., 1976).

239

Clinical Pharmacokinetics of Diuretics

Potassium canrenoate: When lH-potassium canrenoate was given intravenously it rapidly underwent lactonisation to canrenone with subsequent glucuronidation. The concentration of canrenoate glucuronide became higher than that of unconjugated compounds after about 2 hours. It then declined with a half-life of 40 hours. The levels of canrenoate and canrenone equalled each other after about 3 hours (Karim et al.. 197 I). 3.2.4 Plasma Kinetics of Spironolactone, Canrenone and Canrenoate Spironolactone appears to have a plasma tl /2 of a few hours (Abshagen et aI., 1976). The terminal halflife of canrenone was 16.8 ± 2.8h in 5 healthy subjects given a single dose of 200mg spironolactone orally (Karim et aI., I 976a). Almost identical halflives (I9.4 ± 3.6h) of canrenone and canrenoate were found after 400mg spironolactone was given to 5 other volunteers (Sadee et aI., 1974). After 10 days treatment with IOOmg spironolactone twice daily, plasma half-life was unchanged (I 8.1 ± 2.9h). This agrees well with a half-life of 19.2 ± 6.6h in 22 men after 15 days of taking spironolactone 200mg once daily (Karim et aI., I 976c). However, after giving spironolactone 25mg 4 times daily for IS days to the same subjects, plasma half-life of canrenone was significantly shorter, being 12.5 ± 3.4h (Karim et al., 1976c). 3.2.5 Enzyme Induction Treatment with 50mg spironolactone 3 times daily for 7 days reduced the antipyrine half-life in 4 of 9 subjects (Taylor et aI., 1972). When 100mg spironolactone was given daily for 2 weeks, antipyrine half-life was significantly reduced from 12.4 ± 2.4h to 7.6 ± \'7h and the excretion of 4hydroxyantipyrine in urine was increased. There was no change in the volume of distribution. The urinary excretion of 6~-hydroxycortisol also increased significantly (Huffman et aI., 1973). These data indicate that spironolactone is an inducer of hepatic microsomal hydroxylation in man. It does not appear to induce its own metabolism as judged ~rom the unchanged half-

life of canrenone after treatment over 10 days compared with that after a single dose (Sadee et aI., 1974).

3.2.6 Elimination of Spironolactone and its Metabolites Urinary elimination: After lH-spironolactone had been administered orally, Abshagen et al. (I 976) recovered 33.2 ± 2.0 and 52.8 ± 2.3 % of the radioactivity in urine after 21 and 144h respectively. Karim et aI. (I 976a) found only 3 \.6 ± 5.9 % after 120h. This discrepancy might be explained by the high formation of lHP in the study of Karim et al. (J 976a). About half of the urinary radioactivity was extractable with organic solvents. The major lipophilic compounds were the 6~-hydroxy-7a-sul­ phoxide, 6~-hydroxy-7 a-methylsulphonylspironolactone, 7a-sulphoxide and canrenone (Abshagen et aI., 1976; Karim et aI., I 976a). Acidic hydrolysis of the polar fraction converted about 50 % of the radioactivity to the extractable compounds mentioned above, indicating the presence of conjugates. The urinary recovery of radioactivity during 5 days after lH-potassium-canrenoate had been administered intravenously ranged from 42 to 56 %. Approximately 70 % of this radioactivity appeared to be attached to canrenoate glucuronide and about 5 % to canrenone and canrenoate respectively. In addition unidentified metabolites were found (Karim et al., \97 I). Biliary elimination: In patients with bile duct drainage, the biliary .recovery of radioactivity was \6.2 ± 3.\ % after lH-spironolactone was given orally (Abshagen et aI., I 977 a). About 60 % of the radioactivity was attached to polar compounds. The lipophilic constituents in bile were canrenone, 6~-hy­ droxy-7 a-methylsulphinylspironolactone and 6~-hy­ droxy-7 a-thiomethylspironolactone. The pattern of urinary metabolites differed significantly from that in controls. The amount of sulphoxidated metabolites was less and that of 6~-hydroxy-7a-thiomethylspiro­ nolactone and canrenone was higher. Several lines of

Clinical Pharmacokinetics of Diuretics

evidence indicated an enterohepatic circulation of some of the metabolites of spironolactone.

3.2.7 Kinetics in Disease States and Nursing Mothers The plasma half-life of canrenone in 5 patients with liver cirrhosis or chronic hepatitis and in 7 with congestive heart failure averaged 59h (range 32 to 105h), and 37h (I9 to 48h) respectively, which was prolonged compared with that in healthy subjects (Jackson et al., 1977). Abshagen et aI. (I 977b) administered 3H-spironolactone to 6 patients with liver disease before and after 12 days treatment with the drug. Pretreatment plasma half-lives of canrenone and canrenoate did not differ from those in normal subjects. After treatment, plasma half-life of radioactivity had decreased in 4 subjects and increased in 2. The pattern of labelled compounds in the urine was the same as in normal volunteers both before and after treatment. It thus appears .that the kinetics of spironolactone cannot be predicted in the individual patient. The plasma levels of canrenone in a nursing mother being treated with 25mg spironolactone 4 times daily were 144 and 92ng/ ml, 2 and 14.5h respectively after ingestion of the dose. The corresponding levels in milk were 104 and 47ng/ml respectively. A daily intake of 1000mi milk containing 100ng/ml of drug would mean only IOOJ.lg canrenone daily reaching the baby (Phelps and Karim, i 977). 3.2.8 Pharmacological Effects of Metabolites of Spironolactone It has been assumed that canrenone is the only active metabolite of spironolactone in man. When spironolactone and potassium canrenoate were given orally in single doses to healthy volunteers in equimolar amounts, approximately the same levels of canrenone were obtained. Despite this, the effect on renal electrolyte excretion was about three times greater when spironolactone was given. Thus about two thirds. of the effect could not be explained in terms of canrenone. It wa" concluded that there are

240

active sulphur-containing metabolites of spironolactone (Ramsay et aI., 1976). These results differed substantially from those obtained when spironolactone and potassium canrenoate were given continuously. Under such circumstances about 70 % of the effect could be attributed to canrenone (Ramsay et aI., 1977). The apparent discrepancy between the 2 studies can be explained by a longer plasma half-life of canrenone than the presumed active sulphur-containing metabolites leading to a greater accumulation of canrenone. The steady-state plasma levels of canrenone had a weak but significant correlation with the decrease in diastolic blood pressure in hypertensive patients (Henningsen, 1978).

4. Therapeutic Implications The pharmacokinetics of some diuretics (bendroflumethiazide, chlorthalidone, hydrochlorothiazide. frusemide and spironolactone) in healthy subjects has been described adequately. Some data on their pharmacokinetics in pathophysiological states are available but a lot of information is still lacking. For example, are the pharmacokinetics of: (a) bendroflumethiazide and chlorthalidone changed in cardiac failure; (b) bendroflumethiazide, chlorthalidone and spironolactone changed in renal failure, and (c) bendroflumethiazide, chlorthalidone, hydrochlorothiazide and frusemide changed in liver diseases? The kinetic knowledge available at present and its application to practical prescribing is summarised below.

4.1 Gastrointestinal Absorption The gastrointestinal absorption of hydrochlorothiazide varies 3-fold among individuals (sections 1.2.1, 1.2.5). It is evident that such an interindividuaI variability in uptake should be taken into consideration when the diuretic is prescribed. The diminished gastrointestinal uptake of frusemide in renal disease (section 2.1.6) is of clinical importance. Corresponding data are not available for other diuretics.

241

Clinical Pharmacokinetics of Diuretics

4.2 Binding to Blood Elements Frusemide is highly protein bound (section 2.1.3) and it is not unlikely that interactions might occur with other highly protein bound drugs with a low distribution volume and which are bound to the same primary albumin binding site. However, information in this area is still lacking but it should be kept in mind. 4.3 Plasma Kinetics and Elimination The half-lifes of thiazides and diuretics with similar actions vary 15 to 20-fold (sections I. 1.2, I. 5.3). Despite this they are similarly dosed, usually once or twice daily, which appears inadequate. If bendroflumethiazide can be given once or twice daily it is likely that chlorthalidone can be administered every second or third day. Such a dosage principle might decrease the frequency of metabolic side effects. The short duration of action of frusemide and bumetamide is related to rapid elimination. Many patients complain of the short intense diuresis of those diuretics which partially inconveniences some patients. This disadvantage should be possible to avoid with sustained release preparations of fruseide and bumetamide. Spironolactone has shorter half-life when given in several divided doses than when administered in a few doses (section 3.2.4). This indicates that the drug should be given once or twice daily as such a dosage given higher plasma concentrations with the same amount of the diuretic and should also improve patient compliance. Spironolactone is' an inducer of hepatic microsomal enzyme hydroxylation (section 3.2.5) which is important to remember when drugs which undergo hydroxylation such as warfarin and dicoumarol (bishydroxycoumarin) are administered simultaneously with spironolactone.

Note Added in Proof Two recent papers by DahlOf et al. (J 979) and Abshagen et al. (J 979) demonstrate that the

fluorimetric determination of canrenone (Gochman and Gantt, 1962) is highly unspecific. The plasma levels of canrenone after administration of spironolactone appear to be overestimated by a factor of 2 to 5 if they are assayed with fluorimetry instead of HPLC. The terminal half-life of canrenone after administration of a single dose of I OOmg spironolactone to healthy volunteers was significantly longer when determined with HPLC than with fluorimetry, and it averaged 20.1 ± 0.6 and 15.0 ± 0.8 hours respectively. This important new information indicates that the contribution of canrenone to the antimineralocorticoid effect of spironolactone is substantially lower than assumed by Ramsey et al. (J 979).

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Clinical Pharmacokinetics of Diuretics

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