Clinical Pharmacokinetics 2: 93-109 (1977) © ADIS Press 1977

Clinical Pharmacokinetics of Hypnotics D.o. Breimer Department of Pharmacology, Subfaculty of Pharmacy, University of Leiden, Leiden

Summary

The intermittent type of drug action which is desired in hypnotic treatment is fundamentally different from those types of drug treatment where a constant effect is required. Thus, in insomnia, drug action should be restricted to the duration of the night and residual effects should be absent during day-time. During daily administration there should be no accumulation of the drug. These factors taken together, mean that a rapid rate of elimination is of advantage for a hypnotic. In addition, the patient taking a hypnotic expects that sleep is readily obtained and therefore biopharmaceutical factors, especially those promoting a rapid rate of absorption, are crucial for hypnotic drug formulations. Many barbiturates have a relatively long elimination half life, except methohexitone, hexobarbitone and cyclobarbitone. The traditional classification of barbiturates into long-, intermediate- and short-acting compounds bears no relation to the rate of elimination in humans, and for this and other reasons, should be abandoned. Barbiturate salts are rapidly absorbed, in contrast to the free acids. Liver disease tends to decrease the elimination rate of these compounds, whereas renal insufficiency may give rise to accumulation of polar metabolites (e.g. hydroxyamylobarbitone). Methaqualone, too, has a long elimination half life, so that accumulation may occur during daily administration. Absorption of this compound appears to be quite rapid from the formulations investigated. Although the benzodiazepines nitrazepam and ./lurazepam are the most frequently used hypnotics today, information concerning their pharmacokinetics in humans is very limited. The elimination half life of nitrazepam is between 18 and 34 hours, whereas that of unchanged ./lurazepam has not been accurately determined. However, the N-desalkyl metabolite of ./lurazepam, which has pharmacological properties comparable to the parent drug, has an elimination half life of 2 to 4 days. Substantial accumulation of this metabolite occurs during daily administration of./lurazepam. The active metabolite of chloral hydrate (trichloroethanol) is quite rapidly eliminated (t /f2 = 7 to IOh), whereas another important metabolite (trichloroacetic acid, t 1/2 = 4 to 5 days) gives rise to substantial accumulation during chronic administration. The potential protein binding displacement interaction of this compound with coumarin oral anticoagulants such as warfarin, should always be considered in clinical practice.

Clinical Pharmacokinetics of Hypnotics

~

Apart from having effective sleep-inducing properties, the onset and duration of action are essential requirements for a hypnotic drug. Patients who experience difficulty in getting to sleep require a hypnotic drug preparation from which the active substance is rapidly absorbed. If this does not happen, early sleep may not be obtained and the patient is tempted to take a second dose, which may lead to overdosage and prolonged effect. Biopharmaceutical factors governing the rate and extent of drug absorption are crucial in this respect, particularly a rapid rate of absorption. Since hypnotic drugs are most frequently used by non-hospitalised patients, the eNS depressant effect of the drug should have declined sufficiently to be subjectively and objectively unimportant on the morning following the night of drug intake. The ability to carry out various skilled tasks, including driving a motor vehicle, should not be impaired. The kinetics of drug distribution and drug elimination are pertinent factors in relation to the duration of drug action, which should be limited in hypnotic drug therapy. Generally speaking, a rapid elimination rate of a hypnotic drug is~ of aavafitage. The ffiler-mittent type of drug action, which is desired when such a hypnotic substance is used at night, is fundamentally different from those types of drug therapy where steady state plasma levels are required (e.g. antiepileptic agents, cardiac glycosides). Figure I depicts the theoretical plasma level profIle of three hypnotic drugs with different elimination half lives, and possibly with a similar time course of drug concentration in the brain. It is evident that ideal intermittent drug therapy can only be achieved with the drug that has the relatively short half life, in this case heptabarbitone. The risk of prolonged effects after administration of a drug with a much longer half life is far greater and substantial accumulation will occur when such a compound is given every night; e.g. butobarbitone (fig. I). This article reviews the clinical pharmacokinetics of the most important hypnotics in relation to the intermittent type of drug action discussed above. Only those studies where therapeutic doses were applied

94

and the methods of investigation could be expected to give reliable results, will be considered.

1. Barbiturates Although the use of barbiturates has decreased in recent years, there is still an enormous consumption

~ '1

0., -I

.......

Butobarbitone l00mg

Cl

E O~--~----~----~----~--~----~

80~ -I .......

Nitrazepam 5mg

Cl

~O~--~----~----~----~--~----~

III

t~AANJC Eo~\ o Days

1

2

3

i,

5

6

Fig. 1. Plasma level profile of three hypnotics during nightly administration. Calculation of the curves is based upon the experimental concentrations obtained after a single oral dose and taking into account an elimination half life of 6h for heptabarbitone, 24h for nitrazepam and 40h for butobarbitone. In the case of nitrazepam the curves exhibit a biphasic decay (see also fig. 4), and for butobarbitone it is shown that the elimination rate is accelerated after prolonged use owing to enzyme induction (dotted line). The figure illustrates that ideal intermittent therapy can only be achieved with a rapidly eliminated drug (heptabarbitone), whereas accumulation will occur with drugs that are slowly eliminated.

95

Clinical Pharmacokinetics of Hypnotics

of these compounds (Miller, 1973). In table I, pharmacokinetic properties of various barbiturates are given and it appears that the elimination half lives of most compounds is relatively long (fig. 2). Residual CNS depressant effects may occur on the day following the night of drug intake, and have been reported for several of these compounds. The traditional classification of barbiturates into long-, intermediate-, short- and ultrashort-acting categories (pharmacology textbooks), does suggest that their duration of action has been well investigated clinically. However, this classification is based on their duration of hypnosis (anaesthesia) when injected intravenously into rabbits or rats (Tatum, 1939). It is erroneously suggested in Martindale's Extra Pharmacopoeia (1972) that the plasma half lives of the barbiturates classified as having comparable duration of action are similar. For instance hexobarbitone, heptabarbitone, cyclobarbitone, quinalbarbitone (secobarbital), pentobarbitone and butobarbitone have been classified as intermediate-acting barbiturates. However, their average halflives vary from 4.4h for hexobarbitone to 37. 5h for butobarbitone (table I; fig. 2; Breimer, I 976a). Mark (1969) and McQueen (1969) have already seriously questioned the commonly used classification and called it archaic. Every barbiturate, in principle, may be described as long-acting or short-acting, depending on the dose administered. The duration of drug action is determined by the given dose and the rate of biotransformation and excretion, assuming a constant minimal effective concentration. The barbiturates used for intravenous anaesthesia form a separate group, since the redistribution of these highly lipophilic drugs from the brain to other well-perfused tissues is primarily responsible for the rapid recovery from anaesthesia (Price et al.. 1960). It should be recognised however, that anaesthesia is followed by residual €NS depression; the duration of which is mainly determined by the rate of drug elimination. In other words, these compounds are only ultrashortacting with respect to anaesthesia, but not a priori with respect to their sedative-hypnotic action (e.g.

thiopentone). It is desirable to abandon the present barbiturate classification and to reclassify them according to their rate of elimination; the barbiturates suitable for intravenous anaesthesia of short duration should be considered separately.

I. I Methohexitone (methohexital)

This compound is mainly used for intravenous anaesthesia. One of its major advantages is the very rapid recovery from anaesthesia, whereas with thiopentone prolonged CNS-depressant effects are experienced (Whitwam, 1976). This is in agreement with the rapid rate of elimination of methohexitone (Brei mer, I 976b); this compound having the shortest half life and the highest metabolic clearance value of all barbiturates studied (table I). Oral experiments have shown that methohexitone sodium is rapidly absorbed, but its bioavailability was rather low, probably due to a substantial hepatic 'first-pass' metabolism effect (Breimer, 1974). In principle, the rapid elimination of methohexitone should be regarded as favourable when used for intravenous anaesthesia and also in hypnotic drug therapy when applied for sleep induction.

1.2 Hexobarbitone (hexobarbital) Hexobarbitone has been used for intravenous anaesthesia and also in hypnotic drug therapy. Breimer et al. (1975a) have performed a detailed kinetic study of the drug after intravenous administration to man. The elimination half life of the compound was found to be rather short (3 to 7h), which is mainly due to a relatively high metabolic clearance (200 to 300ml/ min). Because of its short halflife, accumulation of hexobarbitone does not take place when given every night (Breimer. 1974). Preliminary experiments also indicated that enzyme induction with this rapidly metabolised barbiturate did not develop readily, provided the dosage interval was long

!I

Table I. Elimination half lives. apparent volumes of distribution and clearance values of barbiturates in mana I

Compound

Dose (mg)

Route of Mean adminis- half life (h) tration

Range (h)

No. of subjects

2.1

Methohexitone

3mg/kg

iv

1.6

1.2 -

Hexobarbitone

600mg or 8mg/kg 400mg

iv

4.4

2.7 -7.3

oral

4.0

2.6 -

150mg 6.6mg/kg

oral oral

7.7 9.7 b

6.2-11.0

Cyclobarbitone

300mg/kg

oral

12.0

Amylobarbitone

3.54mg/kg

iv

130mg 120mg 120mg 125mg Vinylbital

150mg 200mg

Quinalbarbitone (secobarbita!)

oral 3.3mg/kg l00mg oral 150mg/70kg oral

28.9 b 25.0 23.3

Pentobarbitone

50mg 100mg 100mg 100mg

iv iv oral oral

60.3 22.3 29.6 26.5

14.8-27·7 21-46 18-48

200mg

oral

37.5

34-42

i:

Q

I

5'

Mean distribution volume (L/kg)

Reference ean pasma clearance (nll/min)

4

1.13

8:W

Breimer (1976b)

'"n0

14

1.10

21;9

Breimer et al. (1975a)

o·

('i'

!!!.

-c

::T

'"3

0~

5.0!

Breimer and Van Rossum (1973)

5

II

Heptabarbitone

7 6

1.30

8-17

6

0.51

oral oral oral iv

22.7 ± 20.0± 24.8 20.6 23.8 22.8

1.6 (SE) 1.0(SE) 13.7-42.2 16.3-24.3 8-40 i 15-34

7 (males) } 9 (females) 10 5 36 28

oral rectal

23.5 23.8

19.4-28.8 17.6-33.5

"

:!

II ,I

1.38

Breimer and De Boer (1975) Clifford et al. (1974)

3;

Breimer and Win ten (1976)

37

Balasubramanian et al. (1970)

1.27

37 33

Kadar et al. (1973) Inaba and Kalow (1975) Inaba et al. (1976) Endrenyi et al. (1976)

6 6

0.79 0.88

27 32

6 6 6

1.52

53

5 7 10 11

0.99 0.65 0.80

3~

2) 27

Smith et al. (1973) Ehrnebo (1974) Breimer (1976a) Reidenberg et al. (1976)

6

0.78

13

Breimer (1976c)

1.00

<1>

'"

So ::c

-<

-

"0 ~

0

o·

'"

Breimer and De Boer (1976) .

II

Butobarbitone

a b

II

19-34

"

:!

"

Clifford et al. (1974) Breimer( 1976a) Dalton et al. (1976)

Calculations were based on two-compartment kinetics following intravenous administration of the drugs, and generally on single compartment kinetics following oral administration assuming complete bioavailability. Calculations based on whole blood level data instead of plasma concen~rations.

CD

en

97

Clinical Pharmacokinetics of Hypnotics

compared with the half life of the compound. The pharmacokinetic properties of hexobarbitone are such that a satisfactory pharmacokinetic profile can be obtained in hypnotic drug therapy. Rapid absorption of hexobarbitone can only be achieved if its sodium salt is used; the acid form in capsules or tablets is slowly absorbed with peak levels between 2 and 3h (Breimer, 1974). In patients with acute or chronic liver disease (except cholestasis) the rate of elimination of hexobarbitone was found to be very much decreased (Zilly, 1974; Breimer, 1974; Richter et aI., 1977). In many patients, the elimination half life was prolonged 2 to 5-fold, which was mainly attributed to a reduced metabolic clearance. In addition, changes in the distribution of hexobarbitone were observed. Patients with acute hepatitis required less hexobarbitone during intravenous infusion to reach a well-defined stage of CNS depression than healthy controls (Richter et aI., 1972). Plasma levels during infusion increased more rapidly in the patient group, so that at an earlier stage the effective concentration, which appeared to be similar for both groups, was reached (Zilly et aI., 1973). Although this was initially thought to be due to the reduced metabolic clearance, detailed pharmacokinetic investigations have revealed that a reduced volume of the central compartment (initial distribution space) was the main cause of the reduced tolerance to hexobarbitone in the patients with acute hepatitis (Breimer et aI., 1975b). Hexobarbitone contains an asymmetric centre. In practice, the racemic mixture is always used. Breimer and Van Rossum (J 973) have shown that the elimination half life of (-)-hexobarbitone was about 3 times shorter than that of ( + )-hexobarbitone (J .4 and 4.6h respectively). Surprisingly, the opposite was found to occur in rats, with the ( + )-isomer being metabolised faster (Breimer and Van Rossum, 1974). From these experiments, evidence was obtained that the central depressant effect of ( + )-hexobarbitone was greater in both species. At present, these findings only have theoretical significance and do not involve any important consequences when the racemic mixture is used in clinical practice.

1.3 Heptabarbitone (heptabarbitaJ) This barbiturate has a relatively short half life of 6 to I I h. During repetitive administration of heptabarbitone to 4 volunteers (for 8 consecutive nights) no substantial accumulation occurred and ideal intermittent drug therapy in kinetic terms was achieved (fig. I; Breimer and De Boer, 1975). However, residual effects of heptabarbitone have been observed. Thus, Borland and Nicholson (J 974) have shown decrements in performance at the I Oh interval after a 200mg dose and at the 19h interval after a 400mg dose. The average heptabarbitone blood concentrations and performance decrements appeared to be related at each dose. Heptabarbitone is available as the proprietary formulation 'Medomin', but absorption of the active ingredient from these tablets is rather slow; with peak levels between 1.5 and 4h (Brei mer and De Boer, I 975). This finding is consistent with the clinical observations concerning the slow onset of hypnotic activity of 'Medomin' tablets (Weithaler and Biedermann, 1955; Fernandez-Guardiola et aI., 1972). Since rapid absorption is more desirable, Breimer and De Boer (J 975) also investigated the sodium salt of heptabarbitone. Peak levels were now achieved between 20 min and 2h, which is probably due to the good aqueous solubility of the barbiturate.

1.4 Cyclobarbitone (cyclobarbitaJ) Cyclobarbitone is generally used as its calcium salt. Breimer and Winten (1976) demonstrated rapid absorption for two tablet preparations and the aqueous solution (peak level attained within I hour). The extent of bioavailability was comparable for the two tablet preparations, whereas this was found to be 20 % less for the solution. A satisfactory explanation for this unexpected finding is not available so far. Cyclobarbitone has an intermediate elimination half life (8 to 17h). Marked accumulation during a period of nightly administration will not occur, but residual effects may be present the next morning.

98

Clinical Pharmacokinetics of Hypnotics

1.5 Amylobarbitone (amobarbital) The average elimination half lives and clearance values published for amylobarbitone are rather consistent (table 1). The compound has been studied by various groups because it provides a suitable substrate for the study of barbiturate hepatic microsomal oxidation in man. Recently, Endrenyi et al. (1976) performed a genetic study of amylobarbitone elimination based on its kinetics in twins. These data showed that genetic control is exerted on the rate of amylobarbitone metabolism in man. There is great interindividual variatil)n in eHmination ratecwith.half

live~

ranging between II and SOh. In the elder/y, the rate of elimination tends to be reduced compared with younger persons (Irvine et aI., 1974). In patients with chronic liver disease, the elimination half life of amylobarbitone appeared to be significantly prolonged and metabolic clearance reduced in the patients with abnormally low concentrations of albumin in serum (Mawer et aI., 1972). The other patients with liver disease showed no impairment of amylobarbitone metabolism. The clinical response to a single intravenous dose of amylobarbitone was comparable in the two patient groups. In patients with renal insufficiency, the serum concentrations of amylobarbitone were found to be consistently lower in the patient group than in the control group and the average elimination half life was shorter (I 8 versus 23h); Balasubramaniam et aI., 1972). Whether this finding could be attributed to a reduced binding of amylobarbitone to plasma protein in the uraemic patients was not elucidated in the investigation. In these patients the 48h urinary excretion of the major metabolite, hydroxyamylobarbitone, was reduced and the serum concentrations of this compound were consistently raised. During daily administration of 200mg amylobarbitone sodium over 5 consecutive days the serum concentrations of the metabolite rose steadily to a maximum of about 8ug/ml. The concentrations in the control subjects did not exceed 0.5).lg/ml. Impairment of cognitive. function in the patients could be correlated with hydroxyamylobarbitone accumulation. This finding

represents an interesting example of how a relatively inactive polar drug metabolite may become responsible for pronounced pharmacological effects in the presence of renal insufficiency. A study of the elimination kinetics of amylobarbitone in mothers and their newborn infants revealed that similar drug concentrations were found in cord and maternal plasma immediately after delivery (Krauer et a!., 1973). The plasma half life of amylobarbitone was 2 to 5 times as long in the newborn as in the mothers (average values of 16 and 39h respectively). Tnaha and Kalow (1975) have I:hown that the:rl'. ;1:

a linear relationship between amylobarbitone concentrations in saliva and serum; salivary levels were 36 % of serum levels. Protein binding in the same study was determined by equilibrium dialysis at 37°C and the unbound fraction was found to be 40 % (corrected for pH differences between serum and saliva). This is an indication that amylobarbitone concentration in saliva is an indicator of free drug concentration in plasma. Absorption of amylobarbitone sodium seems to be "complete following oral administration (Inaba et ~al., 1976) and it can be derived from some of the studies mentioned before that the sodium salt is rapidly absorbed. CNS depressant effects occur shortly after administration, as evidenced by Hart et al. (1976) in a study of the effects of low doses of amylobarbitone and diazepam on human performance. During that investigation, plasma levels were measured at 3 and 6h following drug administration, but no relationship between change in performance and plasma level was found. Tansella et al. (1975) found slightly higher amylobarbitone concentrations at 10 and 12h after 7 days of nightly drug administration, compared with the concentrations obtained after a single dose. There was a marked interpatient variability, with plasma levels ranging from 0.71 to 12.40Ilg/ml (10th and 12th h mean value) after the first 200mg dose and from 0.92 to 11.40llg/ml after 7 days of therapy. No relationships were found in this study between subjective clinical ratings of hypnotic effect and amylobarbitone plasma concentration, while signifi-

Clinical Pharmacokinetics of Hypnotics

cant correlations were observed between some performance tasks and drug plasma concentrations.

1.6 Quinalbarbitone (secobarbital) Quinalbarbitone, together with pentobarbitone, are the barbiturates most frequently used in general practice. However, the rate of elimination of both compounds in humans is rather slow; the elimination half life for quinalbarbitone being between I 9 and 34h (Clifford et ai., 1974; Breimer, I 976a). Usually, the sodium salt of quinalbarbitone is employed and is rapidly absorbed (Sjogren, 1971; Breimer, 1976a), in contrast to the free acid (Sjogren, 1971; Clifford et ai., 1974). The salt-containing preparations are desirable for a rapid sleep induction. When early peak levels had been attained, a biphasic decline of the plasma concentration was generally observed. The rapid decline of the plasma concentration during the first few hours is probably due to drug distribution into tissues. Only if the brain concentration very closely follows the plasma concentration during the distribution phase, might a relatively short duration of CNS depressant action be possible. However, quinalbarbitone has been shown to impair performance after therapeutic dosage for as long as 22h (McKenzie and Elliott, 1965).

1.7 Pentobarbitone (pentobarbital) The pharmacokinetics of pentobarbitone have been studied by several, investigators, following different routes of administration (table I). The average elimination half life was generally found to lie between 20 and 30h. The results of Smith et al. (1973) showed deviations from these data and although Ehrnebo (] 974) discussed several possible reasons for the discrepancy between his and Smith's results, no satisfactory explanation can be given. Apparently, the metabolism of pentobarbitone is rather

99

slow, with an average clearance value in the same range as that found for amylobarbitone (table I). The overall slow elimination of pentobarbitone in humans increases the risk of persistent effects into the following day. Impairment of performance was reported by Borland and Nicholson (1975) up to 19h after a single dose. Pentobarbitone elimination is quite normal in renal failure (Reidenberg et ai., 1976). Some uraemic patients were shown to have short plasma half lives, but this more probably resulted from low apparent volumes of distribution than from accelerated metabolism of pentobarbitone. Held et ai. (1970) have found that only some patients with liver disease exhibit retarded pentobarbitone elimination. Absorption of pentobarbitone after oral administration is rapid when given as the sodium or calcium salt (Smith et ai., 1973; Breimer, I 976a). In the study of Ehrnebo (] 974), the free acid was also absorbed quite rapidly, but the lag time of absorption appeared to be longer than for the salts. However, Sjogren et al. (1965) have shown that pentobarbitone absorption can also be rather slow when given as free acid. Food may significantly reduce the rate of pentobarbitone absorption, but not the total amount absorbed (Smith et ai., 1973). This is an important observation, since any delay in the time between ingestion of a hypnotic and the onset of sleep would invite repeat dosage of the drug by the patient. Rectal absorption of pentobarbitone results in later attainment of plasma peak levels and lower peak concentrations, whereas the amount absorbed is dependent on the particle size of the active compound (Kingma and Breimer, 1975). There is a linear relationship between pentobarbitone concentrations in saliva and plasma during the elimination phase (De Boer et aI., 1976); salivary levels being approximately one third of plasma levels, which is in agreement with the protein unbound fraction in plasma (Fuchs hofen , 1974). During the absorption phase there was no consistent relationship between plasma and saliva concentrations, which implies that the absorption rate of pentobarbitone cannot be deduced from saliva data alone.

100

Clinical Pharmacokinetics of Hypnotics

1.8 Butobarbitone (butobarbita\)

1.10 Barbiturates: Conclusion

Until recently, butobarbitone was a rather popular barbiturate in European countries. However, its rate of elimination was found to be very slow after single dosage (half lives of 34 to 42h; ~reimer, I 976c). On the basis of urinary excretion data, Gilbert et al. (I 974) found an elimination half life for unchanged butobarbitone of 50.2 and 55.5h in 2 volunteers. During a night's rest of 8h; no more than 15 to 20 % of the administered dose is eliminated and persistent CNS depressant action can be expected during the

Pharmacokinetic studies of barbiturates in man have revealed that only few derivatives may be regarded as suitable for hypnotic therapy. In appropriate dosage, hexobarbitone, heptabarbitone, glutethimide and cyclobarbitone are the compounds that can probably produce a satisfactory plasma level profile of the intermittent type during nightly administration. Only if day-time sedation is required might the other compounds be chosen. In patients with severe liver disease, elimination of

rllly-timp..

"omp ,::>".rhitllr::.tp" m"y hI'. mllrkprlly rp.t"rrlp.rl {I' ~

Thi~

hll~

hp.p.n

~hown

to o",,"r in !,"y_

chological test studies by Bond and Lader (I 972). Figure I shows that accumulation of butobarbitone takes place during nightly administration. It also indicates that after 8 days' treatment, a shorter half life becomes apparent, most probably due to the development of hepatic enzyme induction. The volunteers who took butobarbitone for several consecutive nights all showed a decrease in half life of 20 t'o 25 %. It is obvious that butobarbitone cannot be regarded as a hypnotic of choice. Only if day-time sedation is reqUired, ~ai·be~t·hecase-1nhosp·ita:iised patients~-~ should butobarbitone be considered.

as

I .9 Glutethimide Although glutethimide is not a barbituric acid derivative, but a so-called piperidinedione derivative. it is often considered to have comparable pharmacological actions. Limited information is available with respect to the disposition of glutethimide in man following therapeutic doses. Curry et al. (1971) showed that the absorption rate of glutethimide tablets was very variable, with peak level times between I and 6h; the range of the elimination half life was.5 to 22h for 6 volunteers, with an average value of 11.6h. Similar values were obtained by Kadar et al. (I 974). In principle, intermittent drug action may be achieved with glutethimide when given every night. Plasma level data during a period of repetitive administration, however, have not been published.

hexobarbitone), whereas in patients with renal insufficiency the accumulation of pharmacologically active polar metabolites of some compounds (e.g. amylobarbitone) should be considered. With barbiturate salts. in contrast to the free acids, rapid absorption and onset of hypnotic action may be achieved, although food seems to be an inhibitory factor in this respect; at least in the case of pentobarbitone. The many serious clinical disadvantages of barbiturates have recently been~(liscusse(f (G·ree~ribfitt~an(r Shader, 1972) - for example. suppression of REMsleep, hang-over effects, addiction potentiality, high incidence of death after barbiturate overdosage and development of enzyme induction. Whether these disadvantages apply to every barbiturate to the same extent has never been explored. At present it can only be speculated that some of these effects are less marked with the more rapidly eliminated barbiturates. Phenobarbitone has not been discussed in this review. since its major application is in treatment of epilepsy. In that context, the relatively long half life of phenobarbitone (2 to 6 days; Maynert, 1972) is ofadvantage in obtaining steady state plasma levels during continuous therapy.

2. Methaqualone Methaqualone has been widely used since its introduction in 1958. Brown and Goenechea (1973)

101

Clinical Pharmacokinetics of Hypnotics

10

5.0 Q;

m u 2.0

'"Cl

.2

cyclo 1300mg)

':..i 1.0 --.... Cl

g

.,c

.0

0.5

~c

he pia (200mg)

II>

u

c 0

u

hexo (600mg)

0.2 metho (20'mg)

co

E

'"

co

ll: 0.1

0

5

10

15

20

25

30

10 5.0 Q;

m u
buto 1200mg I

2.0

~--

Cl

.2

.:.i --.... 1.0 Cl

i

c

.g

penloll00mg)

0.5

~

'i:II>

u c 0 u co

0.2

E

~'" 0.1

0

5

10

15

20

25

30

35

Time (h)

Fig. 2. Plasma concentrations of various barbiturates following therapeutic dosage in man (metho = methohexitone; hexo = hexobarbitone; hepta = he pta barbitone; cyclo = cyclobarbitone; buto ;= butobarbitone; vinyl = vinylbital; pento = pentobarbitone; seco ;= secobarbital or quinalbarbitone).

102

Clinical Pharmacokinetics of Hypnotics

have reviewed the pharmacology and biochemistry of blood, and did not accumulate upon repetitive dosing this hypnotic. In one of the first studies on the phar- (Delong et aI., 1976). Somewhat contradictory results macokinetics of methaqualone in humans, plasma were obbained by White et al. (1976), who measured concentrations were determined for 8h after a single concentrations of methaqualone during and following oral dose (Morris et aI., 1972). On the basis of the ob- . 5 daily doses of a combination formulation of methaserved plasma decay during this period, it was con- qualone (250mg), carbromal (300mg) and benaccluded that the elimination half life was 2.6h (fig. 3). tyzine hydrochloride (O.33mg). Their terminal However, a subsequent study by Alvan et al. (I 973), elimination half life was approximately IOh and no who measured plasma levels by a more sensitive significant accumulation of methaqualone was obmethod (mass fragmentography) during IOOh, served. A satisfactory explanation for the discrepancy showed that the distribution half life was between 1.8 between these results and those obtained in earlier and 2. I h, whereas the actual elimination half life was studies is not easy to give. '-xr:lI: ........... uo at OiAh.\ COtllr110A tho ~hC'f"\.rT\tl{"'\n nf _ .. 01 _ ... (1 " .... , ..... , __ r ______ _ ~,

phase indicates a potential for drug accumulation during multiple dosing and this was indeed demonstrated to occur (Alvan et aI., 1974). Nayak et al. (J 974) showed that a steady state methaqualone serum concentration profile was reached within the first week of a 28-day period of daily drug administration. There were no significant changes in the kinetics of absorption, distribution or elimination over this period. Hydroxylated metabolites were not found insignificant amounts in

10

CD

Morris et al. (1972); GC

50 "

& .....................

C'

~~

a __

~A&_

-_~

__

methaqualone from 7 different commercially available preparations, including combination formulations. Peak levels were attained between I and 2h in fasting volunteers and there was a good correlation between peak concentration and hypnotic effect. Similar peak levels of methaqualone were reported by Chemburkar et al. (1976). Since diphenhydramine is often combined with methaqualone, the influence of this compound on the absorption of methaqualone 1Yas. studied separ~JeIy (Williams, 1974a). No signifi-

Alvan et al. (1973) GC-MS

ii::I'.\~ ~ ~ as E c.

c..i ~ 02 c: OJ

8 .§. 01 o

5

10

~~~-~-:r-~---:r:---:r----cc-~-::c::-~--:';---~-x~-=-~--;oc:;--'-=':o. 10 20 30 40 50 60 70 80 90 100

0

Time (hours)

Fig. 3. Plasma concentrations of methaqualone following a single oral dose. In 1972. Morris et al. measured concentrations by a gas chromatographic (GC) method up to Bh. which suggested that the elimination of the drug is very rapid. Subsequently. Alvan et al. (1973) showed that this initial rapid decline is a distribution phase. which is followed by a slow elimination phase. Concentrations in this case were measured by mass fragmentography (GC-MS).

Clinical Pharmacokinetics of Hypnotics

cant influences on the rate of absorption or distribution were observed. At present it is hard to judge whether methaqualone is a suitable hypnotic from the pharmacokinetic point of view. Alvan et al. (1974) found no consistent correlation between plasma levels and sedative emicts, although they suggested that persistent drug effects during day-time should be taken into account, especially during multiple dosage.

3. Benzodiazepines Several benzodiazepine derivatives with antianxiety properties are used at night to facilitate falling asleep easily. Among these, nitrazepam and flurazepam have been widely introduced into clinical practice more specifically as hypnotics. Their principal advantage compared with other hypnotics is a greater margin of safety and the absence of serious drug interactions (Greenblatt and Shader, 1972). In contrast to flurazepam, nitrazepam has not been released as a hypnotic in the United States. In spite of their enormous consumption, the available clinical pharmacokinetic information on these compounds is very limited.

3. I Nitrazepam Rieder (J 973) has studied the pharmacokinetics of nitrazepam in 6 healthy adults after a single intravenous and oral dose of I Omg of the drug. Plasma levels,beginning at 2h following drug administration, were measured by a spectrofluorimetric method. The average elimination half life after intravenous administration was 21 h (range 18 to 24h) and after oral administration 25h (range 2 I to 28h). Owing to the lack of plasma data during the first hour of the experiment, reliable information with respect to drug distribution and the rate of drug absorption cannot be obtained from this investigation. The extent of bioavailability (oral compared with iv) varied from 53 to 94 %, with an average value of 78 %. The con-

103

centrations after oral administration at 2h (maximum) were 68 to I 08ng/mi. In a paper describing a GC method for the assay of nitrazepam in serum, Moller Jensen (I 975) compared the serum levels obtained by two brands of 5mg nitrazepam-containing tablets in 15 healthy.volunteers. The average elimination half lives (based upon concentrations at 7, 24 and 48h) were 28 ± 11 h (SO) in the experiment with brand I and 25 ± 6h (SO) with brand II. Peak levels for both brands were obtained at 2h (25 to 50ng/mI), whereas bioavailability turned out to be comparable. Breimer et ai. (1977) developed a capillary GC method for the determination of unchanged nitrazepam in plasma and has been used for investigations of the pharmacokinetics and bioavailability of nitrazepam after oral administration of different dosage forms. Plasma samples were collected at regular intervals from l5min up to 80h following drug administration. Preliminary results have revealed that the rate of absorption of the proprietary formulation 'Mogadon' was quite variable among 7. fasting healthy volunteers, with peak levels between 0.5 and 5h. The absorption phase was generally followed by a distribution phase lasting approximately 2 to 3h, during which plasma levels decreased about 2-fold (fig. 4). After this period, a slight increase in plasma concentration (possibly due to an enterohepatic recirculation of the active substance) occurred, followed by a first-order elimination phase (fig. 4). The average half life was 27h (range 18 to 34h), which is comparable with the values published previously. In figure I, the plasma concentration profile during daily dosage of nitrazepam has been simulated. The elimination half life is rather long when considered in relation to its relatively short intended duration of action and slight accumulation occurs when this hypnotic is taken every night. Published data suggest that nitrazepam causes persistent impairment of performance on the day following intake of a therapeutic dose (Malpas et ai., 1970; Bond and Lader, 1972; Borland and Nicholson, 1975), which is in agreement with the persistence of the active compound in the body. Despite its favourable pharmacodynamic properties, the kinetically desirable

Clinical Pharmacokinetics of Hypnotics

104

type of intermittent hypnotic drug therapy cannot be achieved with nitrazepam. It is interesting to note that in man, nitrazepam is metabolised in part by nitro-reduction to the amine followed by acetylation (Beyer and Sadee, 1969) and this acetylation step has been shown to be under the control of the same genetic polymorphism as sulphadimidine (Karim and Price Evans, 1976).

3.2 Flurazepam

drochloride has recently been reviewed (Greenblatt et aI., 1975). Kaplan et al. (1973) studied the kinetics of flurazepam and its metabolites (hydroxyethyl deriva- . tive and N-I-desalkyl derivative) during dosage of 30mg daily. Only trace amounts of unchanged drug were measured, whereas the hydroxyethyl metabolite was measurable for several hours after each dose. Accumulation of this metabolite was not observed. The major metabolite was the N-I-desalkyl derivative,

were 10 to 22ng/ ml blood and after 2 weeks of treatment they rose to 49 to 142ng/ml (fig. 5). Hence, significant accumulation of this metabolite occurs during continuous administration of flurazepam. Since the desalkylated metabolite of flurazepam has psychopharmacological activity similar to flurazepam in animal studies (Randall and Kappell, 1973), it might contribute to the hypnotic and persistent sedative action of flurazepam. Residual effects after a single dosage have been reported (Bixler et aI., 1973; Borland and Nicholson, 1975; Bond and Lader, 1975). Kales et al. (l976) have discussed the effectiveness of flurazepam as evaluated in sleep laboratory studies, where peak effectiveness of the drug did not result until the second and third consecutive drug nights.

4. Chloral Hydrate Chloral hydrate is probably the oldest synthetic

~~~which~was~de.m9Jl~tr
half life ranging from 47 to 100h in the 4 healthy volunteers. Peak concentrations after a single dose

m

E 40

flinear scale

administered in aqueous solution or in the form of a pro-drug (e.g. chloral betaine, dichloralphenazone and

log scale

100

VI

'"

50

Ci

Nitrazepam 5mg

.::::'.30 Cl

..3-

~c. 20

10

~ L~-=

~ ·c

g

u

t ~ ~ 28 h

5

10

00

2

4

~6~~8~'

:1

+0-~-~2'0::--~-·~4:r:'0-~-:r:60·~-80

Time (h)

Fig. 4. Plasma concentrations of nitrazepam following a single 5mg oral dose (tablet). The initial rapid decay is probably due to distribution of the compound into tissues, whereas the dip in the curve may be caused by enterohepatic recirculation or a redistribution process (Breimer et aI., 1977).

Clinical Pharmacokinetics of Hypnotics

105

N- desalkyflurazepam 80

60

-g ~

20

...J

........

~

0

o

-I

5

t

II tit t t t 10

20

15

Days

25

Fig. 5. Blood level profile of N-desalkylflurazepam in 2 healthy subjects during and following repeated nightly administration of 30mg flurazepam hydrochloride. The arrows indicate the time of drug intake (after Kaplan et aI., 1973).

triclofos). Marshall and Owens (J 954) were the first to study the fate of chloral hydrate in humans and they provided evidence that the metabolite trichloroethanol is responsible for the hypnotic action following oral administration. The average plasma half life of this compound in humans was found to be 8.2h (Sellers et ai., 1973). Other metabolites of chloral hydrate are trichloroacetic acid and trichloroethanolglucuronide. Garrett and Lam,bert (1973) have conducted an extensive study on the kinetics of trichloroethanol and these metabolites in dogs . Breimer et al. (J 974b) developed a GC method with electron captur'e detection, employing head-space analysis, for the simultaneous determination of chloral hydrate and the various metabolites in blood. Chloral hydrate was administered orally or rectally to healthy volunteers (15mg/kg or I,OOOmg). In figure

50

20

---."".--.---_.

TCA

10

TCE

t'h. B.Sh

'2

4

6

10

1'2

Time (h)

Fig. 6. Blood concentrations of trichloroethanol (TCE), trichloroethanol glucuronide (TCE-Glu) and trichloroacetic acid (TCA) following oral administration of a single dose of chloral hydrate (1 ,275m g) in aqueous solution, Unchanged chloral hydrate could not be detected, despite the availability of a sensitive assay method. The elimination half·life of TCS in this subject appeared to be 100h (after Breimer, 1974).

Clinical Pharmacokinetics of Hypnotics

6 an example of the curves obtained is given. Unchanged parent drug could not be detected, not even in the first few samples which were taken every 10 min after drug administration. Peak levels of trichloroethanol as well as trichloroethanolglucuronide were reached 20 to 60 min after oral administration of aqueous drug solution. The average blood half life of trichloroethanol measured for 5 volunteers was 8.0h (range 7.0 to 9.5h). For trichloroethanolglucuronide, an average half life of 6.7h (range 6.0 to 8.0h) was determined. After rectal administration of chloral hydrate (I ,000mg dissolved in 2 to 3ml sesame oil or polyethyleneglycoI), the half lives of the trichloroethanol and its conjugate were in the same range as after oral administration (Breimer, 1974). The half life of trichloroacetic acid was found to be about 4 days and substantial accumulation was observed during nightly administration of chloral hydrate (up to I OOmg/L blood). Sellers and Koch-Weser (197\) have demonstrated that trichloroacetic acid displaces from binding sites on serum albumin, and there have been a few reports of a small change (potentiation) in anticoagUIinf ·control· with- warfarin, although other· investigators have found no change. On the other hand, dicoumarol action has been reported to be inhibited by chloral hydrate (see Verstraete and Verwilghen, 1976). This type of drug interaction should be given consideration when chloral hydrate is prescribed simultaneously with coumarin oral anticoagulants (Boston Collaborative Drug Surveillance Program, 1973). Whether the relatively high concentrations of trichloroacetic acid as such are harmful to the patient, is unknown. Obviously, the formation ofa metabolite with such kinetic behaviour is undesirable. A good deal of attention has also been paid to the interaction between chloral hydrate and alcohol. Concurrent administration gives rise to an enhanced central depressant effect, which may be explained by higher trichloroethanol, and at the same time higher alcohol, blood concentrations (Kaplan et al. 1967; Sellers et al., 1972a,b). As already mentioned, peak levels of trichloroethanol are rapidly achieved if chloral hydr-

106

ate is administered in aqueous solution, which is desirable for the rapid induction of sleep. Because of the bad taste and gastric irritation which is quite often caused by this preparation, chloral hydrate is administered rectally. For this route of administration the vehicle appears to be a critical factor. Significantly higher trichloroethanol blood levels are obtained when chloral hydrate is incorporated in a hydrophilic polyethylene glycol base, compared with lipophilic vehicles (Brei mer et aI., 1973). Chloral hydrate may also be available in various capsule formulations and the two distributed in Holland have been investigated (Breimer et aI., 1974a). One preparation was claimed to induce sleep readily, the second to release the active ingredient after about 4 hours. However, peak trichloroethanol concentrations were found to occur as long as 2 to 4h after administration of the first product and between 3 and 9h after the second (5 volunteers). Obviously, the claims of the manufacturer of these products cannot be accepted. Blood level data are pertinent in order to judge whether a certain drug preparation is suitable to be used for a special category of insomniacs. From the pharmacokinetic point of view; cliloral hydrate seems to liave satisfactory properties, since the half life of its active metabolite is rather short. However, the formation of trichloroacetic acid is a matter of concern, especially when chloral hydrate is prescribed together with highly protein bound drugs.

References Alvan. G.; Ericsson. 0.; Levander. S. and Lindgren. J.E.: Plasma concentrations and effects of methaqualone after single and multiple oral doses in man. European Journal of Clinical Pharmacology 7: 449-454 (1974). Alvan. G.; lindgren. J.-E.; Bogentoft. C. and Ericsson. 0.: Plasma kinetics of methaqualone in man after single oral doses. European Journal of Clinical Pharmacology 6: 187-190 (1973). Balasubramaniam. K.; Lucas. S.B.; Mawer. G.E. and Simons. P.J.: The kinetics of amylobarbitone metabolism in healthy men and women. British Journal of Pharmacology 39: 564-572 (1970). Balasubramaniam. K.; Mawer. G.E.; Pohl. J.E.F. and Simons. P.J.G.: Impairment of cognitive function associated with hy-

Clinical Pharmacokinetics of Hypnotics

. droxyamylobarbitone accumulation in patients with renal insufficiency. British Journal of Pharmacology 45: 360-367 (1972). Beyer, K.-H. von and Sadee, W.: Spektrophotometrische Bestimmung von 5-phenyl- IA-benzodiazepine Derivaten und Untersuchungen uber den Metabolismus des Nitrazepam. Arzneimittel-Forschung (Drug Research) 19: 1929-1931 (1969). Bixler, E.O.; Kales, A.; Tan, T.L. and Kales, J.D.: The effects of hypnotic drugs on performance. Current Therapeutic Research 15: 13-24 (1973). Bond, AJ. and Lader, M.H.: Residual effects of.hypnotics. Psychopharmacologia 25: 117-132 (1972). Bond, AJ. and Lader, M.H.: Residual effects of flurazepam. British Journal of Clinical Pharmacology 2: 143-150 (1975). Borland, R.G. and Nicholson, A.N.: Human performance after a barbiturate (heptabarbitone). British Journal of Clinical Pharmacology I: 209-215 (1974). Borland, R.G. and Nicholson, A.N.: Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance. Brit. J. Clin. Pharmacol. 2: 9-17 (1975). Boston Collaborative Drug Surveillance Program: Interaction between chloral hydrate and warfarin. New England 10urnal of Medicine 286: 53-55 (1972). Breimer, D.O.: Pharmacokinetics of hypnotic drugs. Studies on the pharmacokinetics and biopharmaceutics of barbiturates and chloral hydrate in man. Ph.D.-thesis, University of Nijmegen, The Netherlands (1974). Breimer, D.O.: Pharmacokinetic and biopharmaceutical aspects of hypnotic drug therapy; in Gouveia, Tognoni and Van der Kleijn (Eds). Clinical Pharmacy and Clinical Pharmacology, p. 17-42 (Elsevier/North-Holland Biomedical Press, Amsterdam 1976a). Breimer, D.O.: Pharmacokinetics of methohexitone following intravenous infusion in humans. British 10urnal of Anaesthesia 48: 643-649 (1976b). Breimer, D.O.: Pharmacokinetics of butobarbital after single and multiple oral doses in man. European Journal of Clinical Pharmacology 10: 263-271 (1976c). Breimer, D.O. and De Boer, A.G.: Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium in man after oral administration. European Journal of Clinical Pharmacology 9: 169-178 (1975). Breimer, D.O. and De Boer, A.G.: Pharmacokinetics and relative bioavailability of vinylbital in man after oral and rectal administration. Arzneimillel-Forschung (Drug Research) 26: 448-454 (1976). Breimer, D.O.; De Boer, A.G.; Rost-Kaiser, J. and Bracht, H.: Unpublished investigations (1977). Breimer, D.O.; Cox, H.L.M. and Van Rossum, 1.M.: Relative bioavailability of chloral hydrate after rectal administration of different dosage forms. Pharmaceutisch Weekblad 108: 1101-1110 (1973).

107

Breimer, D.O.; Cox, H.L.M. and Van Rossum, J.M.: Trichloroethanol blood level profile in man after oral administration of chloraldurat capsules. Pharmaceutisch Weekblad 109: 1041-1045 (I 974a). Breimer, D.O.; Honhoff. c.; Zilly, W.; Richter, E. and Van Rossum, J.M.: Pharmacokinetics of hexobarbital in man after intravenous infusion. Journal of Pharmacokinetics and Biopharmaceutics 3: I-II (I 975a). Breimer, D.O.; Ketelaars, H.CJ. and Van Rossum, 1.M.: The determination of chloral hydrate, trichloroethanol and trichloroacetic acid in blood and urine, employing head-space analysis. Journal of Chromatography 88: 55·63 (I 974b). Breimer, D.O. and Van Rossum, J.M.: Pharmacokinetics of( + )-, (-)- and (± -hexobarbitone in man after oral administration. Journal of Pharmacy and Pharmacology 25: 762-764 (1973). Breimer, D.O. and Van Rossum, J.M.: Pharmacokinetics of the enantiomers of hexobarbital studied in the same rat and in the same isolated perfused rat liver. European 10urnal of Pharmacology 26: 321-330 (1974). Breimer, D.O. and Winten, M.A.C.M.: Pharmacokinetics and relative bioavailability of cyclobarbital calcium in man after oral administration. European 10urnal of Clinical Pharmacology 9: 443-450 (( 976). Breimer, D.O.; Zilly, W. and Richter, E.: Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery. Clinical Pharmacology and Therapeutics 18: 443-440 (I 975b). Brown, S.S. and Goenechea, S.: Methaqualone: Metabolic, kinetic and clinical pharmacologic observations. Clinical Pharmacology and Therapeutics 14: 314-323 (1973). Chemburkar, P.B.; Smyth, R.D.; Buehler, J.D.; Shah, P.B.; Joslin, R.S.; Polk, A. and Reavy-Cantwell, N.H.: Correlation between dissolution characteristics and absorption of methaqualone from solid dosage forms. Journal of Pharmaceutical Sciences 65: 529-533 (1976). Clifford, J.M.; Cookson, 1.H. and Wickham, P.E.: Absorption and clearance of secobarbital, heptabarbital, methaqualone and ethinamate. Clinical Pharmacology and Therapeutics 16: 376-389 (1974). Curry, S.H.; Riddall, D.; Gordon, 1.S.; Simpson, P.; Binns, T.B.; Rondel, R.K. and McMartin, c.: Disposition of glutethimide in man. Clin. Pharmacol. Ther. 12: 849-857 (1971). Dalton, W.S.; Martz. R.; Rodda. B.E.; Lemberger, L. and Forney. R.B.: Influence of cannabidiol on secobarbital effects and plasma kinetics. Clinical Pharmacology and Therapeutics 20: 695-700 (1976). De Boer. A.G.; Gubbens-Stibbe. I.M. and Breimer. D.O.: Application of pentobarbital salivary excretion data for pharmacokinctic and biopharmaceutical studies in man. Abstract Dutch Federation Proceedings, p. 127, Amsterdam (1976). Delong, A.F.; Smyth, R.D.; Polk, A.; Nayak. R.K. and ReaveyCantwell. N.H.: Blood levels of methaqualone in man following chronic therapeutic doses. Archives Internationales de Pharmacodynamie et de Therapie 222: 322-331 (1976).

108

Clinical Pharmacokinetics of Hypnotics

Ehrnebo. M.: Pharmacokinetics and distribution propenies of pentobarbital in humans following oral and intravenous administration. Journal of Pharmaceutical Sciences 63: 1114-1118 (1974). Endrenyi. L.; Inaba. T. and Kalow. W.: Genetic study of amobarbital elimination based on its kinetics in twins. Clinical Pharmacology and Therapeutics 20: 701-714 (1976). Fernandez-Guardiola. A.: Lerdo de Tejada. A.; Contrevas. C.; Salgado. A. and Ayala. F.: Polygraphic study in man to differentiate sleep-inducing action of hypnotics. Psychopharmacologia 26: 285-295 (J 972). Fuchshofen. M.: Methodische Untersuchungen zur Plasmabindungskapazitat fur Pentobarbital bei lebergesunden Normalpersonen und bei Patienten mit Lebererkrankungen. M.D.-thesis. University of Wurzburg. German Federal Republic (J 974),

.. _. .

Dh.,. ......... n,. ..... L-; ...... t; .... ~ _ _ _ _ A • • •_ _

~.a~._

... r

Kaplan. H.L.: Forney. R.B.; Hughes. F.W. and Jain. N.C.: Chloral hydrate and alcohol metabolism in human subjects. Journal of Forensic Sciences 12: 295-303 (1967). Kaplan. S.A.: ue Silva. J.A.F.: Jack. M.L.: Alexander. K.: Strojny. N.: Weinfeld. R.E.: Puglisi. c.Y. and Weissman. L.: Blood level proflle in man following chronic oral administration of flurazepam hydrochloride. Journal of Pharmaceutical Sciences 62: 1932-1935 (1973). Karim. A.K.M.B. and Price Evans. D.A.: Polymorphic acetylation of nitrazepam. Journal of Medical Genetics I 3: 17-19 (1976). Kingma. J.J. and Breimer. D.D.: The influence of particle size on the bioavailability of pentobarbital sodium from suppositories. Abstract 35th International Congress of Pharmaceutical Sciences. Dublin ( 1975). v ......... ,... ..

.................

D. .......

T\. __ l"l'__

r<

...................

.............

11

__ .. IU.·lIU03.

''l1:11!_~

"

r. ...

r"L." ....

I

l.J\.JU'I;'y.

~1_ .. _ no .. .HI .......-1Ul\;. 1'\0..:-',.;

C.T. and Hawkins. D.F.: Elimination kinetics of amobarbital trichloroethanol and metabolites and interconversions among in mothers and their newborn infants. Clinical Pharmacology variously referenced pharmacokinetic· parameters. Journal of Pharmaceutical Sciences 62: 550-572 (1973). and Therapeutics 14: 442·447 (1973). Gilben. J.N.T.; Natunen. T.: Powell. J.W. and Saunders. L.: A McQueen. E.G.: Management of unconscious poisoned patients. British Medical Journal 2: 177-178 (1969). kinetic study of human urinary excretion results for butobarMalpas. A.: Rowan. AJ.: Joyce. C.R.B. and Scott. D.F.: Persisbitone and its metabolites. Journal of Pharmacy and Phartent behavioural and electro-encephalographic changes after macology 26: Suppl.: 16P-23P (1974). single doses of nitrazepam and amylobarbitone sodium. British Greenblatt. OJ. and Shader. R.1.: The clinical choice of sedativeMedical Journal 2: 762-764 (1970). hypnotics. Annals of Internal Medicine 77: 91-100 (1972). Greenblatt. D.J.: Shader. R.t. and Koch-Weser. J.: Flurazepam Mark. L.c.: Archaic classification of barbiturates. Clinical Pharmacology and Therapeutics 10: 287-291 (1969). hydrochloride. Clinical Pharmacology and Therapeutics 17: 1-14 (1975). . Marshall. E.K. and Owens. A.H.: Absorption. excretion and __ - ---Hart. 1.:HiiC H.M.~Y;' c.E~:--wilk;;;;-~;~R.T~~d P;;-~k: A:W:~~---~-;t~boli~~fa;~~;C~hlor~lh;dr~;;~d~rkhl~;,~~th~n~I~-Bulle~i,;~-~ -The effects of low doses of amylobarbitone sodium and diazepam on human performance. British Journal of Clinical Pharmacology 3: 289-298 (1976). Held. H.: von Oldershausen. H.F. and Remmer. H.: Der Abbau von Pentobarbital bei Leberschaden. K1inische Wochenschrift 48: 565-567 (1970). Inaba. T. and Kalow. W.: Salivary excretion of amobarbital in man. Clinical Pharmacology and Therapeutics 18: 558-562 (1975). Inaba. T.; Tang. B.K.: Endrenyi. L. and Kalow. W.: Amobarbital - a probe of hepatic drug oxidation in man. Clinical Pharmacology and Therapeutics 20: 439-444 (1976). Irvine. R.E.; Grove. J.: Toseland. P.A. and Trounce. J.R.: The effect of age on the hydroxylation of amylobarbitone sodium in man. British Journal of Clinical Pharmacology I: 41-43 (\ 974). Kadar. D.: Inaba. T.: Endrenyi. L.: Johnson. G.E. and Kalow. W.: Comparative drug elimination capacity in man - glutethimide. amobarbital. antipyrine and sulfinpyrazone. Clinical Pharmacology and Therapeutics 14: 552-560 (t 974). Kales. A.; Bixler. E.O.; Scharf. M. and Kales. J.D.: Sleep laboratory studies of flurazepam: A model for evaluating hypnotic drugs. Clinical Pharmacology and Therapeutics 19: 576-583 (t 976).

of the Johns Hopkins Hospital 95: 1-18 (1954). Manindale: The Extra Pharmacopoeia (26th ed): Blacow and Wade (Eds). p. 891 (The Pharmaceuti~a1 Press. London 1972). Mawer. G.E.: Miller. N.E. and Turnberg. L.A.: Metabolism of amylobarbitone in patients with chronic liver disease. British Journal of Pharmacology 44: 549-560 (1972). Maynen. E.W.: Phenobarbital. mephobarbital and metharbital. Absorption. Distribution. Excretion and Biotransformation: in Woodbury. Penry and Schmidt (Eds) Antiepileptic Drugs. p. 303-317. (Raven Press. New York 1972). McKenzie. R. E. and Elliott. L. L.: Effects of secobarbital and damphetamine on performance during a simulated air mission. Aerospace Medicine 36: 774-779 (t 965). Miller. R.R.: Drug surveillance utilizing epidemioiogic methods: a repon from the Boston Collaborative Drug Surveillance Program. American journal of Hospital Pharmacy 30: 584-592 (1973).

.

Moller. Jensen. K.: Determination of nitrazepam in serum by gasliquid chromatography. Application in bioavailability studies. journal of Chromatography III: 389-396 (t 975). Morris. R.N.: Gunderson. G.A.: Babcock. S.W. and Zarostinski. J.F.: Plasma levels and absorption of methaqualone after oral administration to man. Clinical Pharmacology and Therapeutics 13: 719-723 (\ 972).

Clinical Pharmacokinetics of Hypnotics

Nayak. R.K.; Smyth. R.D.; Chamberlain. J.H.; Polk. A.; Delong. A.F.; Herczeg. T.; Chemburkar. P.B.; Joslin. R.S. and Reavey-Cantwell. N.H.: Methaqualone pharmacokinetics after single- and. multiple-dose administration in man. Journal of Pharmacokinetics and Biopharmaceutics 2: 107-121 (1974). Price. H.L.; Kovnat. P.1.; Safer. J.N.; Conner. E.H. and Price. M.L.: The uptake of thiopental by body tissues and its relation to the duration of hypnosis. Clinical Pharmacology and Therapeutics I: 16-22 (1960). Randall. L.O. and Kappell. B.: Pharmacological activity of some benzodiazepines and their metabolites; in Garattini. Mussini and Randall (Eds) The Benzodiazepines. p. 27-51 (Raven Press. New York 1973). Reidenberg. M.M.; Lowenthal. D.T.; Briggs. W. and Gasparo. M.: Pentobarbital elimination in patients with poor renal function. Clinical Pharmacology and Therapeutics 20: 67-71 (1976). Richter. E.; Zilly. W. and Brachtel. D.: Zur Frage der Barbiturattoleranz bei Patienten mit akuter Hepatitis. Deutsche Medizinische Wochenschrift 97: 254-255 (1972). Richter. E.; Zilly. W.; Breimer. D.D.: Pharmacokinetics of hexobarbital in patients with intra- and extrahepatic cholestasis. Manuscript in preparation (1977). Rieder. J.: Plasma levels and derived pharmacokinetic characteristics of unchanged nitrazepam in man. ArzneimittelForschung (Drug Research) 23: 212-218 (1973). Sellers. E.M.; Carr. G.; Bernstein. J.G.; Sellers. S. and KochWeser. J.: Interaction of chloral hydrate and ethanol in man. II. Hemodynamics and performance. Clinical Pharmacology and Therapeutics 13: 50-58 (I 972b). Sellers. E.M. and Koch-Weser. J.: Kinetics and clinical importance of displacement of warfarin from albumin by acidic drugs. Annals of the New York Academy of Sciences 179: 213-225 (1971). Sellers. E.M.; Lang. M.L.; Cooper. S.D. and Koch-Weser. J.: Chloral hydrate and tridofos metabolism. Clinical Pharmacology and Therapeutics 14: 147 (1973). Sellers. E.M.; Lang. M.; Koch-Weser. J.; leBlanc. E. and Kalant. H.: Interaction of chloral hydrate and ethanol in man. I. Metabolism. Clinical Pharmacology and Therapeutics 13: 37-49 (I 972a). Sjogren. J.: Importance of pharmaceutical formulation for drug absorption. Acta Pharmacologica et Toxicologica 29. Suppl. 3: 68-80 (1971). Sjogren. J.; Solvell. L. and Karlsson. I.: Studies on the absorption rate of barbiturates in man. Acta Medica Scandinavica 178: 553-559 (1965).

109

Smith. R.B.; Dittert. L.W.; Griffen. W.O. Jr.. and Doluisio. J.T.: Pharmacokinetics of pentobarbital after intravenous and oral administration. Journal of Pharmacokinetics and Biopharmaceutics I: 5-16 (1973). Tansella. M.; Siciliani. 0.; Burti. L.; Schiavon. M. and Zimmermann-Tansella. Ch.: N-Desmethyldiazepam and amylobarbitone sodium as hypnotics in anxious patients. Plasma levels. clinical efficacy and residual effects. Psychopharmacologia 41 : 81-85 (1975). Tatum. A.L.: The present status of the barbiturate problem. Physiological Reviews 19: 472-502 (1939). Verstraete. M. and Verwilghen. R.: Haematological disorders: Drug interactions with oral anticoagulants; in Avery (Ed) Drug Treatment. p. 681-687 (ADlS Press. Sydney; Publishing Sciences Group. Acton; Churchill Livingstone. Edinburgh 1976). Weithaler. K. and Biedermann. G.: Klinische und experimentelle Untersuchungen uber ein Schlafmittel. Medizinische Klinik 50: 2155-2158 (1955). White. c.; Doyle. E.; Chasseaud. L.F. and Taylor. T.: Serum concentrations of methaqualone after repeated oral doses of a combination formulation to human subjects. European Journal of Clinical Pharmacology 10: 343-347 (1976). Whitwam. J.G.: Methohexitone (Editorial). British Journal of Anaesthesia 48: 617 -619 (I 976). Williams. M.E.; Davis. S.S.; Poxon. R.; Kendall. M.J. and Mitchard. M.: The influence of diphenhydramine on the absorption of methaqualone in man. British Journal of Clinical Pharmacology I: 259-264 (1974a). Williams. M.E.; Kendall. M.J.; Mitchard. M.; Davis. S.S. and Poxon. R.: Availability of methaqualone from commercial preparations: in vitro and in vivo studies in man. British Journal of Clinical Pharmacology I: 99-105 (197 4b). Zilly. W.: Arzneimittelelimination (Hexobarbital. Tolbutamid. Digoxin und ~-Methyldigoxin) bei Patienten mit akuter Hepatitis und Leberzirrhose. M.D.-thesis. University of Wurzburg. Federal Republic of Germany (1974). Zilly. W.; Brachtel. D. and Richter. E.: Hexobarbitalplasmaspiegel bei Patienten mit akuter Hepatitis wah rend kontinuierlicher Hexobarbital-Infusion. Klinische Wochenschrift 51: 346-347 (\ 973).

Author's address: Prof. Douwe D. Breimer. Department of Pharmacology. Subfaculty of Pharmacy. Sylvius Laboratories. Wassenaarseweg 72. Leiden (The Netherlands).