Acta pharmacol. et toxicol. 1975, 36, 33-38.
From the Department of Pharmacology, University of Turku, and the Psychiatric Clinic of Turku Municipal Hospital, Turku, Finland
Human and Animal Study on Elimination from Plasma and Metabolism of Diazepam after Chronic Alcohol Intake BY
R. Sellman, J. Kanto, E. Raijola and A. Pekkarinen (Received May 13, 1974; Accepted August 17, 1974)
Abstract: Very significantly lower concentrations of diazepam at 15 minutes and 1 hour after 10 mg intravenous diazepam injection were found in chronic alcoholic patients in comparison t o healthy controls. Compared to 13 healthy controls a more rapid elimination of diazepam from the plasma of 14 chronic alcoholic patients during their alcohol-free period was observed. The alcoholics had a smaller concentration of the diazepam main metabolite, N-demethyldiazepam, and at 3 hours this difference was significant. The concentrations of free plasma oxazepam as a metabolite of diazepam, were not observed after a single dose of diazepam either in the alcoholics or in volunteers. A more rapid elimination of diazepam after 5 mg/kg intraperitoneally in the plasma of rats pretreated with ethyl alcohol (15 % in drinking water for 3 weeks) was found than in the control rats. Pretreatment of rats with ethyl alcohol increased significantly the concentration of the hydroxylated metabolite, free oxazepam, in the plasma, but not of the demethylated metabolite, N-demethyldiazepam. Key-words: Alcoholism - diazepam enzyme induction.
-
drug distribution and metabolism
-
The benzodiazepine psychosedative drugs are used in the treatment of ethyl alcohol withdrawal, because their depressing effect on respiration is slight in alcohol withdrawal, and they have little effect on REM sleep & GREENBLA~T 1972; KAIM 1973; or autonomic functions (GREENBLATT KELLYet al. 1973). However, with higher doses, they can sometimes cause habituation and, as a sign of dependence, certain withdrawal symptoms 1970). (HOLMBERG 1967; PETERS& SEIDELL In a previous study SELLMAN et al. (1973) found reduced concentrations of plasma diazepam during an alcohol-free period of chronic alcoholic patients, following a 10 mg oral dose of diazepam, possibly due to disturbances in the gastro-intestinal absorption phase of diazepam. The purpose of this study of parenteral administration of diazepam was
34
R.SELLMAN et al.
to obtain more information about the mechanism responsible for the low concentrations of diazepam in the plasma of some alcoholic patients in the oral phase of absorption. Similarly, experimental studies were carried out on rats after pretreatment with ethyl alcohol.
Materials and Methods Ten mg of diazepam was administered intravenously to 14 chronic alcoholic patients in their alcohol-free period and t o 13 healthy volunteers. The mean age of the alcoholics (all men) was 40 years and that of the volunteers (4 women and 9 men) 27 years. All the alcoholics were heavy drinkers and their excessive use of alcoholic drinks continued during the period of 10-20 years. They were taken into the Psychiatric Clinic of Turku Municipal Hospital 1-3 days before the administration of diazepam. Two of the patients had latent pulmonary tuberculosis. There was no knowledge of other possible diseases, and getting any exact anamnesis from them was quite difficult. They were without medication for at least 12 hours before the experiment. Before coming into the hospital, none of the patients had received diazepam. The only drug used by two alcoholics before diazepam administration was paraldehyde. The concentrations of diazepam and its metabolites in the plasma after a 10 mg dose of diazepam given intravenously were followed as can be seen in fig. 1. Diazepam, its main metabolite, N-demethyldiazepam, and free oxazepam in the plasma were determined gas chromatographically by the method for determining diazepam, published earlier (KANGAS et al. 1974). A eSNi-detector was used. The required volume of the plasma for drug estimation was 0.5 ml. Diazepam and all its metabolites had different retention times. The recovery percentage of this method was 95 ? 2 (n=10) for plasma diazepam, 92 f 2 (n=10) for plasma N-demethyldiazepam, and 93 ? 3 (n= 10) for free plasma oxazepam. The rats were pretreated with 15 % ethyl alcohol in place of drinking water for 21 days. This treatment has been shown to cause an induction of microsomal drugmetabolizing enzymes in rat liver (SINGLEVICH & BARBORIAK 1971). Before receiving diazepam, the rats were kept without ethyl alcohol medication for one day, after which diazepam (5 mg/kg of body weight) was given intrapentoneally to albino rats weighing between 200-300 grams. Diazepam and its metabolites in 0.5 ml of plasma were measured by the same method as before, seen in fig. 2. The recovery percentages are the same as in human plasma. The control rats received diazepam only. The statistical analyses of the results have been performed using the Student's t-test.
Results Human studies. Fig. 1 shows the plasma concentrations of diazepam and N-demethyldiazepam both in the alcoholic patients and in the controls. The alcoholics had very highly significantly lower plasma concentrations of diazepam at 15 minutes and 1 hour (P < 0.001), and significantly lo'wer plasma concentrations of diazepam at 3 and 24 hours (P < 0.05) after an intravenous
35
DIAZEPAM ELIMINATION IN ALCOHOLICS Concentrationof diazepam nghnl
e31= Controls(n-13)
n=Alcoholics(n=l4)
600 500
Concentration of N-demethyldiazepam nglml
400
300
c 0
*
200
T
100
T
14
1
3
9
%hours
1
0 T
h Ill 3
9
2G hours
Fig. 1. Plasma concentrations of diazepam and N-demethyldiazepam after a 10 mg dose of diazepam intravenously in chronic alcoholic patients and in healthy volunteers. Mean k S. E. M. (nglml).
Concentralm of diazepam nglml
9 o o Tp
Concentration of free oxarcpam nghl
800 700 a=Controls (n.13) O=Alcoholic rah(n.10)
600 500
Concentrationof N-demethyldiazepam
400
300
200 100 Smin 3
h lh
2h
3h
4h 6h Time
5min 30min lh
Time
Fig. 2. Plasma concentrations of diazepam, N-demethyldiazepam, and free oxazepam after an intraperitoneal injection of diazepam (5 mg/kg of body weight) in experimental rats pretreated with ethyl alcohol and in control rats. Mean k S. E. M. (nglml).
36
R.SELLMAN et al.
injection of 10 mg diazepam as compared to the controls. The alcoholics had lower plasma N-demethyldiazepam concentrations at 3 hours (P < 0.05), 9 hours and 24 hours (P < 0.10) after the injection of diazepam than the controls. There were no measurable amounts of free plasma oxazepam either in the alcoholics or in the controls after a single dose of diazepam. Experimental studies. In fig. 2 the plasma concentrations of diazepam, N-demethyldiazepam, and free oxazepam, both in the rats pretreated with ethyl alcohol and in the controls, can be seen. There were significantly lower concentrations of plasma diazepam in the rats pretreated with ethyl alcohol than in the controls, especially shortly after the intraperitoneal injection of diazepam (5 mg/kg {of body weight) at 5 minutes and also later on at 3 hours (P < 0.01), and at 4 hours (P < 0.05). No significant difference was observed in the N-demethyldiazepam concentrations in the plasma of the rats, which had been pretreated with ethyl alcohol, and in the control rats. On the contrary, those rats which had been pretreated with ethyl alcohol, had higher concentrations of the hydroxylated metabolite, free plasma oxazepam, at 5 minutes (P < 0.05), 1 hour (P< 0.01), and 2 hours (P < 0.001) after the injection of diazepam than the controls.
Discussion The lower initial concentrations of diazepam in plasma of the chronic alcoholic patients might be an interesting point to study, since it is well known that alcoholics, when sober, have an increased resistance to the pharmacological effects of sedative drugs (RUBIN& LIEBER1971). This can be due to a cross-tolerance, or to an increased distribution of diazepam into the tissues other than the central nervous system. After a parenteral administration of diazepam in our study, the alcoholics had initially clearly lower peak concentrations of plasma diazepam, nearly one half of those in the controls, possibly indicating a faster initial disappearance rate of diazepam from the plasma of alcoholics than from that of the controls. In this study about twice as high peak concentrations of diazepam in plasma were shown in the controls than in the chronic alcoholic patients at 15 minutes after intravenous injection, which was also seen after the oral administration of diazepam in the previous study (SELLMAN et al. 1973, and in this issue). It was suggested that after oral administration of diazepam the lower concentrations of diazepam in the plasma of alcoholics, observed at the absorption phase of diazepam, may be due to disturbances
DIAZEPAM ELIMINATION IN ALCOHOLICS
37
in the gastro-intestinal mucosa or liver functions. The accelerated distribution of diazepam after its parenteral administration from the plasma of the chronic alcoholic patients might be due to a vasodilation or an accelerated blood circulation. As is known, during the period of withdrawal alcoholics can sometimes develop tachycardia, vasodilatation and even a rise in blood pressure. These circulatory changes, especially a peripheral vasodilatation, could cause an increased distribution of diazepam from the plasma to tissues. The increased metabolism of certain drugs in alcoholics is often indicated by their shortened half-lives in blood. However, the number of drug metabolites has not been measured in alcoholics in many studies (KATERet al. 1969; PARKER1970). Both in human and animal studies ethyl alcohol has been shown to be an inducer of the hepatic micrmomal enzymes of drug metabolism (RUBIN& LIEBW1968 & 1971; SINGLEVICH & BARBORIAK 1971). As evidence of the induction phenomenon of drugs, an increase in the T Our human number of drug metabolites has been shown ( P R E S C ~1969). study showed no increase in the metabolite concentrations after a single dose of diazepam in the chronic alcoholic patients. On the contrary, there was some indication of lower plasma concentrations of N-demethyldiazepam when compared to the controls. The gradually lower concentrations of N-demethyldiazepam in the plasma of the chronic alcoholic patients than in that of the controls, may indicate a decreased demethylation of diazepam in the liver, or an increased distribution of N-demethyldiazepam from the plasma. Since all the alcoholics were heavy drinkers, it is possible that the reduced concentrations of N-demethyldiazepam may be due to disturbance in liver functions. There was not even a measurable amount of free plasma oxazepam either in the alcoholic patients or in the controls. Our experimental studies of plasma diazepam concentrations in rats seem to support the results of human studies. Thus the lower initial concentrations of diazepam after its intraperitoneal injection and the disappearance curve of plasma diazepam after the pretreatment of rats with ethyl alcohol is similar in the alcoholics and in the controls. In our opinion, an increased hydroxylation of diazepam to oxazepam in rats, as an indication of enzyme induction, and caused by ethyl alcohol administration, cannot solely explain this great initial difference in the plasma diazepam concentrations. In man there was no indication of an increased metabolic rate of diazepam. The plasma concentrations of Ndemethyldiazepam were even lower in the alcoholics than in the controls, and no free plasma oxazepam was observed after a single injection of diazepam in man. Thus there may be an increased distribution of diazepam from plasma both in man and in the rat, due to ethyl alcohol pretreatment.
38
R.SELLMAN et al. REFERENCES
Greenblatt, D. J. & M. Greenblatt: Which drug for alcohol withdrawal? J. Clin. Pharmacol. 1972, 12, 429-431. Holmberg, G.: Missbrukas diazepam? Lakartidningen 1967, 66, 67. Kaim, S. C.: Benzodiazepines in the treatment of alcohol withdrawal states. In: The benzudiazepines. Eds.: S . Garattini, E. Mussini, and L. 0. Randall. Raven Press, New York 1973, pp. 571-575. Kangas, L., A. Pekkarinen, C. Sourander & E. Raijola: A comparative gaschromatographic study on absorption of diazepam tablets in man. Ann. Clin. Res. 1974, 6, Suppl. 11, 12-20. Kater, R. M. H., G. Roggin, F. Tobon, P. Zieve & F. L. Iber: Increased rate of clearance of drugs from the circulation of alcoholics. Amer. J. Med. Sci. 1969, 258, 35-39. Kelly, D., R. Pick & C.-N. Chen: A psychological and physiological evaluation of the effects of intravenous diazepam. Brit. J . Psychiat. 1973, 122,419-426. Parker, W. J.: Alcohol-drug interactions. J . Amer. Pharm. Ass. 1970, NS 10, 664-677. Peters, U. H. & M. Seidell: Medikamentenmissbrauch und Sucht bei Diazepam. Arzneimittelforsch. (Drug Res.) 1970, 20, 876-877. Prescott, L.: Pharmacokinetic drug interactions. Lancet 1969, 2, 1239-1243. Rubin, E. & C. Lieber: Hepatic microsomal enzymes in man and rat: induction and inhibition by ethanol. Science 1968, 162, 690691. Rubin, E. & C. Lieber: Alcoholism, alcohol and drugs. Science 1971, 172, 1097-1102. Sellman, R., A. Pekkarinen & E. Raijola: Reduced plasma diazepam concentrations in chronic alcoholic patients following an oral absorption test of diazepam. Acta physiol. Scand. 1973, Suppl. 396, 224. Singlevich, T. E. & J. J. Barboriak Ethanol and induction of microsomal drugmetabolizing enzymes in the rat. Toxicol. Appl. Pharmacol. 1971, 20, 284-290.
From the Department of Pharmacology, University of Turku, and the Psychiatric Clinic of Turku Municipal Hospital, Turku, Finland
Human and Animal Study on Elimination from Plasma and Metabolism of Diazepam after Chronic Alcohol Intake BY
R. Sellman, J. Kanto, E. Raijola and A. Pekkarinen (Received May 13, 1974; Accepted August 17, 1974)
Abstract: Very significantly lower concentrations of diazepam at 15 minutes and 1 hour after 10 mg intravenous diazepam injection were found in chronic alcoholic patients in comparison t o healthy controls. Compared to 13 healthy controls a more rapid elimination of diazepam from the plasma of 14 chronic alcoholic patients during their alcohol-free period was observed. The alcoholics had a smaller concentration of the diazepam main metabolite, N-demethyldiazepam, and at 3 hours this difference was significant. The concentrations of free plasma oxazepam as a metabolite of diazepam, were not observed after a single dose of diazepam either in the alcoholics or in volunteers. A more rapid elimination of diazepam after 5 mg/kg intraperitoneally in the plasma of rats pretreated with ethyl alcohol (15 % in drinking water for 3 weeks) was found than in the control rats. Pretreatment of rats with ethyl alcohol increased significantly the concentration of the hydroxylated metabolite, free oxazepam, in the plasma, but not of the demethylated metabolite, N-demethyldiazepam. Key-words: Alcoholism - diazepam enzyme induction.
-
drug distribution and metabolism
-
The benzodiazepine psychosedative drugs are used in the treatment of ethyl alcohol withdrawal, because their depressing effect on respiration is slight in alcohol withdrawal, and they have little effect on REM sleep & GREENBLA~T 1972; KAIM 1973; or autonomic functions (GREENBLATT KELLYet al. 1973). However, with higher doses, they can sometimes cause habituation and, as a sign of dependence, certain withdrawal symptoms 1970). (HOLMBERG 1967; PETERS& SEIDELL In a previous study SELLMAN et al. (1973) found reduced concentrations of plasma diazepam during an alcohol-free period of chronic alcoholic patients, following a 10 mg oral dose of diazepam, possibly due to disturbances in the gastro-intestinal absorption phase of diazepam. The purpose of this study of parenteral administration of diazepam was
34
R.SELLMAN et al.
to obtain more information about the mechanism responsible for the low concentrations of diazepam in the plasma of some alcoholic patients in the oral phase of absorption. Similarly, experimental studies were carried out on rats after pretreatment with ethyl alcohol.
Materials and Methods Ten mg of diazepam was administered intravenously to 14 chronic alcoholic patients in their alcohol-free period and t o 13 healthy volunteers. The mean age of the alcoholics (all men) was 40 years and that of the volunteers (4 women and 9 men) 27 years. All the alcoholics were heavy drinkers and their excessive use of alcoholic drinks continued during the period of 10-20 years. They were taken into the Psychiatric Clinic of Turku Municipal Hospital 1-3 days before the administration of diazepam. Two of the patients had latent pulmonary tuberculosis. There was no knowledge of other possible diseases, and getting any exact anamnesis from them was quite difficult. They were without medication for at least 12 hours before the experiment. Before coming into the hospital, none of the patients had received diazepam. The only drug used by two alcoholics before diazepam administration was paraldehyde. The concentrations of diazepam and its metabolites in the plasma after a 10 mg dose of diazepam given intravenously were followed as can be seen in fig. 1. Diazepam, its main metabolite, N-demethyldiazepam, and free oxazepam in the plasma were determined gas chromatographically by the method for determining diazepam, published earlier (KANGAS et al. 1974). A eSNi-detector was used. The required volume of the plasma for drug estimation was 0.5 ml. Diazepam and all its metabolites had different retention times. The recovery percentage of this method was 95 ? 2 (n=10) for plasma diazepam, 92 f 2 (n=10) for plasma N-demethyldiazepam, and 93 ? 3 (n= 10) for free plasma oxazepam. The rats were pretreated with 15 % ethyl alcohol in place of drinking water for 21 days. This treatment has been shown to cause an induction of microsomal drugmetabolizing enzymes in rat liver (SINGLEVICH & BARBORIAK 1971). Before receiving diazepam, the rats were kept without ethyl alcohol medication for one day, after which diazepam (5 mg/kg of body weight) was given intrapentoneally to albino rats weighing between 200-300 grams. Diazepam and its metabolites in 0.5 ml of plasma were measured by the same method as before, seen in fig. 2. The recovery percentages are the same as in human plasma. The control rats received diazepam only. The statistical analyses of the results have been performed using the Student's t-test.
Results Human studies. Fig. 1 shows the plasma concentrations of diazepam and N-demethyldiazepam both in the alcoholic patients and in the controls. The alcoholics had very highly significantly lower plasma concentrations of diazepam at 15 minutes and 1 hour (P < 0.001), and significantly lo'wer plasma concentrations of diazepam at 3 and 24 hours (P < 0.05) after an intravenous
35
DIAZEPAM ELIMINATION IN ALCOHOLICS Concentrationof diazepam nghnl
e31= Controls(n-13)
n=Alcoholics(n=l4)
600 500
Concentration of N-demethyldiazepam nglml
400
300
c 0
*
200
T
100
T
14
1
3
9
%hours
1
0 T
h Ill 3
9
2G hours
Fig. 1. Plasma concentrations of diazepam and N-demethyldiazepam after a 10 mg dose of diazepam intravenously in chronic alcoholic patients and in healthy volunteers. Mean k S. E. M. (nglml).
Concentralm of diazepam nglml
9 o o Tp
Concentration of free oxarcpam nghl
800 700 a=Controls (n.13) O=Alcoholic rah(n.10)
600 500
Concentrationof N-demethyldiazepam
400
300
200 100 Smin 3
h lh
2h
3h
4h 6h Time
5min 30min lh
Time
Fig. 2. Plasma concentrations of diazepam, N-demethyldiazepam, and free oxazepam after an intraperitoneal injection of diazepam (5 mg/kg of body weight) in experimental rats pretreated with ethyl alcohol and in control rats. Mean k S. E. M. (nglml).
36
R.SELLMAN et al.
injection of 10 mg diazepam as compared to the controls. The alcoholics had lower plasma N-demethyldiazepam concentrations at 3 hours (P < 0.05), 9 hours and 24 hours (P < 0.10) after the injection of diazepam than the controls. There were no measurable amounts of free plasma oxazepam either in the alcoholics or in the controls after a single dose of diazepam. Experimental studies. In fig. 2 the plasma concentrations of diazepam, N-demethyldiazepam, and free oxazepam, both in the rats pretreated with ethyl alcohol and in the controls, can be seen. There were significantly lower concentrations of plasma diazepam in the rats pretreated with ethyl alcohol than in the controls, especially shortly after the intraperitoneal injection of diazepam (5 mg/kg {of body weight) at 5 minutes and also later on at 3 hours (P < 0.01), and at 4 hours (P < 0.05). No significant difference was observed in the N-demethyldiazepam concentrations in the plasma of the rats, which had been pretreated with ethyl alcohol, and in the control rats. On the contrary, those rats which had been pretreated with ethyl alcohol, had higher concentrations of the hydroxylated metabolite, free plasma oxazepam, at 5 minutes (P < 0.05), 1 hour (P< 0.01), and 2 hours (P < 0.001) after the injection of diazepam than the controls.
Discussion The lower initial concentrations of diazepam in plasma of the chronic alcoholic patients might be an interesting point to study, since it is well known that alcoholics, when sober, have an increased resistance to the pharmacological effects of sedative drugs (RUBIN& LIEBER1971). This can be due to a cross-tolerance, or to an increased distribution of diazepam into the tissues other than the central nervous system. After a parenteral administration of diazepam in our study, the alcoholics had initially clearly lower peak concentrations of plasma diazepam, nearly one half of those in the controls, possibly indicating a faster initial disappearance rate of diazepam from the plasma of alcoholics than from that of the controls. In this study about twice as high peak concentrations of diazepam in plasma were shown in the controls than in the chronic alcoholic patients at 15 minutes after intravenous injection, which was also seen after the oral administration of diazepam in the previous study (SELLMAN et al. 1973, and in this issue). It was suggested that after oral administration of diazepam the lower concentrations of diazepam in the plasma of alcoholics, observed at the absorption phase of diazepam, may be due to disturbances
DIAZEPAM ELIMINATION IN ALCOHOLICS
37
in the gastro-intestinal mucosa or liver functions. The accelerated distribution of diazepam after its parenteral administration from the plasma of the chronic alcoholic patients might be due to a vasodilation or an accelerated blood circulation. As is known, during the period of withdrawal alcoholics can sometimes develop tachycardia, vasodilatation and even a rise in blood pressure. These circulatory changes, especially a peripheral vasodilatation, could cause an increased distribution of diazepam from the plasma to tissues. The increased metabolism of certain drugs in alcoholics is often indicated by their shortened half-lives in blood. However, the number of drug metabolites has not been measured in alcoholics in many studies (KATERet al. 1969; PARKER1970). Both in human and animal studies ethyl alcohol has been shown to be an inducer of the hepatic micrmomal enzymes of drug metabolism (RUBIN& LIEBW1968 & 1971; SINGLEVICH & BARBORIAK 1971). As evidence of the induction phenomenon of drugs, an increase in the T Our human number of drug metabolites has been shown ( P R E S C ~1969). study showed no increase in the metabolite concentrations after a single dose of diazepam in the chronic alcoholic patients. On the contrary, there was some indication of lower plasma concentrations of N-demethyldiazepam when compared to the controls. The gradually lower concentrations of N-demethyldiazepam in the plasma of the chronic alcoholic patients than in that of the controls, may indicate a decreased demethylation of diazepam in the liver, or an increased distribution of N-demethyldiazepam from the plasma. Since all the alcoholics were heavy drinkers, it is possible that the reduced concentrations of N-demethyldiazepam may be due to disturbance in liver functions. There was not even a measurable amount of free plasma oxazepam either in the alcoholic patients or in the controls. Our experimental studies of plasma diazepam concentrations in rats seem to support the results of human studies. Thus the lower initial concentrations of diazepam after its intraperitoneal injection and the disappearance curve of plasma diazepam after the pretreatment of rats with ethyl alcohol is similar in the alcoholics and in the controls. In our opinion, an increased hydroxylation of diazepam to oxazepam in rats, as an indication of enzyme induction, and caused by ethyl alcohol administration, cannot solely explain this great initial difference in the plasma diazepam concentrations. In man there was no indication of an increased metabolic rate of diazepam. The plasma concentrations of Ndemethyldiazepam were even lower in the alcoholics than in the controls, and no free plasma oxazepam was observed after a single injection of diazepam in man. Thus there may be an increased distribution of diazepam from plasma both in man and in the rat, due to ethyl alcohol pretreatment.
38
R.SELLMAN et al. REFERENCES
Greenblatt, D. J. & M. Greenblatt: Which drug for alcohol withdrawal? J. Clin. Pharmacol. 1972, 12, 429-431. Holmberg, G.: Missbrukas diazepam? Lakartidningen 1967, 66, 67. Kaim, S. C.: Benzodiazepines in the treatment of alcohol withdrawal states. In: The benzudiazepines. Eds.: S . Garattini, E. Mussini, and L. 0. Randall. Raven Press, New York 1973, pp. 571-575. Kangas, L., A. Pekkarinen, C. Sourander & E. Raijola: A comparative gaschromatographic study on absorption of diazepam tablets in man. Ann. Clin. Res. 1974, 6, Suppl. 11, 12-20. Kater, R. M. H., G. Roggin, F. Tobon, P. Zieve & F. L. Iber: Increased rate of clearance of drugs from the circulation of alcoholics. Amer. J. Med. Sci. 1969, 258, 35-39. Kelly, D., R. Pick & C.-N. Chen: A psychological and physiological evaluation of the effects of intravenous diazepam. Brit. J . Psychiat. 1973, 122,419-426. Parker, W. J.: Alcohol-drug interactions. J . Amer. Pharm. Ass. 1970, NS 10, 664-677. Peters, U. H. & M. Seidell: Medikamentenmissbrauch und Sucht bei Diazepam. Arzneimittelforsch. (Drug Res.) 1970, 20, 876-877. Prescott, L.: Pharmacokinetic drug interactions. Lancet 1969, 2, 1239-1243. Rubin, E. & C. Lieber: Hepatic microsomal enzymes in man and rat: induction and inhibition by ethanol. Science 1968, 162, 690691. Rubin, E. & C. Lieber: Alcoholism, alcohol and drugs. Science 1971, 172, 1097-1102. Sellman, R., A. Pekkarinen & E. Raijola: Reduced plasma diazepam concentrations in chronic alcoholic patients following an oral absorption test of diazepam. Acta physiol. Scand. 1973, Suppl. 396, 224. Singlevich, T. E. & J. J. Barboriak Ethanol and induction of microsomal drugmetabolizing enzymes in the rat. Toxicol. Appl. Pharmacol. 1971, 20, 284-290.
