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Lack of tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide (librium) elimination
GASTROENTEROLOGY
1981;81:547-51
Lack of Tolerance and Rapid Recovery of Cimetidine-Inhibited Chlordiazepoxide (Librium) Elimination RASHMI V. PATWARDHAN, RAYMOND F. JOHNSON, ALICIA P. SINCLAIR, STEVEN SCHENKER, and
K. V. SPEEG, JR. Department of Medicine, Vanderbilt University School of Medicine, Administration Medical Center, Nashville, Tennessee
Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p < 0.001) after 24 h of cimetidine, by 57% (p < 0.001) after 30 days of cimetidine and returned to normal after cimetidine was stopped for 48 h. In the absence of changes in volume of distribution, these changes resulted in proportional increases in the elimination half-life (tHB)after 24 h and 30 days cimetidine treatment, and returned to pretreatment values after stopping cimetidine. In addition, the impaired chlordiazepoxide elimination was accompanied by inhibition of generation and subsequent elimination of N-desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.
Received February 20,1981. Accepted April 24,1981. Address requests for reprints to: Dr. K. V. Speeg, Jr., B-230 Veterans Administration Medical Center, 1310 24th Avenue South, Nashville, Tennessee 37203. This work was supported by the Veterans Administration and National Institutes of Health Grant AAOO267, and by funds from Smith Kline and French Laboratories, Philadelphia, Pennsylvania. 8 1981 by the American Gastroenterological Association 001sSOe5/81/090547-059I2.50
and Veterans
Drug-drug interaction between cimetidine and other drugs has been the focus of several investigations in the last 2 yr. Cimetidine in therapeutic doses has been shown to impair the elimination of warfarin (with resultant increase in prothrombin time), antipyrine (l), diazepam (2), and chlordiazepoxide (3). These agents are known to require microsomal oxidation for elimination. In contrast, cimetidine was found to have no effect upon the elimination of lorazepam and oxazepam in humans (4,s); these benzodiazepines are known to be eliminated by glucuronidation. Animal studies have also demonstrated that cimetidine inhibits microsomal oxidative drug metabolism, both in vitro (6,7) and in vivo (7,8). Chlordiazepoxide (Librium; Roche Laboratories, Nutley, N.J.), a benzodiazepine sedative, is frequently used in the treatment of anxiety states, alcohol withdrawal, and peptic ulcer disease. Hence the simultaneous use of chlordiazepoxide and cimetidine would be a frequent occurrence. We have previously demonstrated that therapeutic doses of cimetidine taken for 1 wk impaired the clearance of chlordiazepoxide (3). We report studies to define the time-course of this inhibition, to assess whether tolerance to this inhibition occurs with continued cimetidine use, and finally to determine how rapidly the inhibitory effect is reversed.
Method Chlordiazepoxide disposition and elimination was studied in 7 healthy, nonsmoking subjects (5 males, 2 females), 22-43 yr old. Each had a normal history, physical examination, and laboratory profile (SMA-12, CBC). No subject had been taking other medications for at least 2 wk
before and throughout the study. Each subject gave written informed consent, and the study was approved by the
548
PATWARDHAN
GASTROENTEROLOGY
_ B.
CHLORDIAZEPOXIDE
A.
6ooO
ET AL.
CHLORDIAZEPOXIDE AFTER
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t
Vol. 81. No. 3
24
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CIMETIDINE HOURS
Figure 1. Plasma concentration/time profiles of chlordiazepoxide and N-desmethylchlordiazepoxide in 7 normal subjects for the four phases of the study. The solid line depicts chlordiazepoxide decay and the dashed line, the accumulation of Ndesmethylchlordiazepoxide. Each point represents the mean f SEM of seven studies.
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Institutional jects.
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CHLODIAZEPOXIDE AFTER
for the Protection
I 0
I 10
STOPPING 40
HOURS
1 20
I 30
CIMETIDINE
1 40
I 50
J 60
(HOURS)
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Sub-
for Study
Chlordiazepoxide disposition and elimination was studied on four separate occasions in all subjects in the following sequence: (a) baseline study (no pretreatment); (b) cimetidine, 1200 mg in 4 equally divided doses, was given 24 h before and throughout the 56 h of blood collection (acute study); (c) cimetidine, 1200 mg in similarly divided doses, was given for 30 days before and throughout the 56 h of blood collection (chronic study); and (d) two days after stopping cimetidine (recovery study). Chlordiazepoxide was prepared immediately before each study as a 5-mg/ml solution in normal saline and was given intravenously over 1 min into an antecubital vein at
a dose of 0.6 mg/kg. From an indwelling cannula placed in the opposite arm (kept patent with normal saline), blood samples were collected into heparinized tubes at 0, 5, 10, 15, 30, and 60 min and then at 2, 3, 4, 5, 6, 8, 12, 24, 32, 40, and 56 h after injection. Plasma levels of chlordiazepoxide and its first metabolite, IV-desmethylchlordiazepoxide, were measured by high-performance liquid chromatography (9), and plasma chlordiazepoxide binding was measured by equilibrium dialysis on plasma samples taken at zero time in each study (lo). Plasma chlordiazepoxide levels declined biexponentially with time, and the data from each subject were analyzed accordingly, after weighting by a coefficient of variation of 0.05, according to a two-compartmental open model and by a modified version of the least-squares iterative digital computer program-SAAM23 (ll),to the func-
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GASTROENTEROLOGY
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Figure 2. Elimination half-life and free clearance in each subject during the four phases of the study. The horizontal bars represent mean values.
ies have shown that a single dose of cimetidine (60120 mg/kg) inhibits the elimination of aminopyrine in the rat (8); there was impaired diazepam elimination after 1000 mg of cimetidine in 5 divided doses in humans (13). We have now demonstrated that cimetidine inhibits the elimination of chlordiazepoxide after a l-day pretreatment, and this effect persists after a l-mo cimetidine treatment, indicating that tolerance does not develop to this inhibitory effect. This is similar to the effects of oral contraceptive steroids (14) and antabuse (15), but unlike the tolerance observed after alcohol (16,17). Furthermore, the cimetidine-induced inhibition was rapidly reversible (after withdrawing cimetidine for 48 h) implying absence of morphologic and structural hepatic damage by cimetidine. This supports studies with rat hepatic microsomes (6,7), which have demonstrated reversible spectral binding of cimetidine to microsomal suspensions in vitro. Chlordiazepoxide is almost exclusively eliminated after oxidative metabolism in the liver and has a relatively low extraction ratio and plasma clearance (20-30 ml/min). Its removal from plasma is thus de-
Vol. 81, No. 3
pendent on the functional capacity of mixed-function oxidase in the liver microsomes. As it is the free (unbound) drug that is available for metabolism, the free clearance of the drug best reflects the capacity of the liver to metabolize this low-clearance drug. In addition to measuring the elimination of chlordiazepoxide from plasma, we measured the first metabolite of chlordiazepoxide degradation and found that the generation and elimination of the pharmacologically active metabolite was also impaired by cimetidine. Although we have not measured subsequent degradative products of the metabolic sequence of chlordiazepoxide, these findings suggest that additional oxidative steps after N-demethylation of chlordiazepoxide may also be inhibited by cimetidine. These observations are consistent with findings recently reported for diazepam (2,5). The steady-state level of drug achieved (therapeutic drug level desired on chronic dosing) is determined by its plasma clearance while the time required to achieve and maintain this level is determined by its elimination half-life. Thus the coadministration of cimetidine and chlordiazepoxide (and presumably other drugs) would lead to higher steady-state levels, and it may be necessary either to reduce the dose of chlordiazepoxide, or to space dosing further apart-especially in the elderly and in patients with kidney and liver disease who may be more sensitive to the sedative effects of chlordiazepoxide and cimetidine per se. In summary, the present study demonstrates that the inhibitory effect is rapid in onset, that no tolerance develops, and that recovery is rapid upon cimetidine withdrawal.
References 1. Serlin MJ, Sibeon
2. 3.
4.
5.
6. 7.
8.
RB, Mossman S, et al. Cimetidine: interaction with oral anticoagulants in man. Lancet 1979;2:317-9. Klotz V, Reimann I. Delayed clearance of diazepam due to cimetidine. N Engl J Med 1980;302:1012-4. Desmond PV, Patwardhan RV, Schenker S, et al. Cimetidine impairs the elimination of chlordiazepoxide in man. Ann Intern Med 1980;93:266-8. Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 1980;79:912-6. Klotz LJ, Reimann I. Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam. Eur J Clin Pharmacol 1980;18:517-20. Rendic S, Sumjic V, Toso R, et al. Interaction of cimetidine with liver microsomes. Xenobiotica 1979;9:555-64. Pelkanen 0, Puureinen J. The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem Pharmacol 1980;29:3075-80. Desmond PV, Patwardhan RV, Parker R, et al. Effect of cimetidine and other antihistamines on the elimination of aminopyrine, phenacetin and caffeine. Life Sci 1979;28:1261-8.
September
1961
CIMETIDINE INHIBITION OF CHLORDIAZEPOXIDE
9. Peat MA, Finkle BS, Deyman ME. High pressure liquid chromatographic determination of chlordiazepoxide and its major metabolite in biological fluids. J Pharm Sci 1979;66:1467-6. 10.Johnson RF, Schenker S, Roberts RK, et al. Plasma binding of benzodiazepines in humans. J Pharm Sci 1979;66:1320-2. 11.Berman M, Weiss MF. SAAM Manual, Public Health Service Manual No. 1703.Washington, D.C.: U.S. Government Printing Office, 1966. 12.Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975;55:347-59. 13. Klotz U, Antilla V-J, Reimann J. Cimetidine/diazepam inter-
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action (lett). Lancet 1979;2:699. 14. Patwardhan RV, Desmond PV, Johnson RF, et al. Impaired elimination of caffeine by oral contraceptive steroids. J Lab Clin Med 1980;95:693-6. 15. Lang M. Marselos M, Torronen R. Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. I. Mixedfunction oxygenase. Chem-Biol Interactions 1978;15:267-76. 16.Sellers EM, Holloway MR. Drug kinetics and alcohol ingestion. Clinical Pharmacokinet 1978;3:44&52. 17. Iber FL. Drug metabolism in heavy consumers of ethyl alcohol. Clin Pharmacol Ther 1977;22:735-42.
1981;81:547-51
Lack of Tolerance and Rapid Recovery of Cimetidine-Inhibited Chlordiazepoxide (Librium) Elimination RASHMI V. PATWARDHAN, RAYMOND F. JOHNSON, ALICIA P. SINCLAIR, STEVEN SCHENKER, and
K. V. SPEEG, JR. Department of Medicine, Vanderbilt University School of Medicine, Administration Medical Center, Nashville, Tennessee
Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p < 0.001) after 24 h of cimetidine, by 57% (p < 0.001) after 30 days of cimetidine and returned to normal after cimetidine was stopped for 48 h. In the absence of changes in volume of distribution, these changes resulted in proportional increases in the elimination half-life (tHB)after 24 h and 30 days cimetidine treatment, and returned to pretreatment values after stopping cimetidine. In addition, the impaired chlordiazepoxide elimination was accompanied by inhibition of generation and subsequent elimination of N-desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.
Received February 20,1981. Accepted April 24,1981. Address requests for reprints to: Dr. K. V. Speeg, Jr., B-230 Veterans Administration Medical Center, 1310 24th Avenue South, Nashville, Tennessee 37203. This work was supported by the Veterans Administration and National Institutes of Health Grant AAOO267, and by funds from Smith Kline and French Laboratories, Philadelphia, Pennsylvania. 8 1981 by the American Gastroenterological Association 001sSOe5/81/090547-059I2.50
and Veterans
Drug-drug interaction between cimetidine and other drugs has been the focus of several investigations in the last 2 yr. Cimetidine in therapeutic doses has been shown to impair the elimination of warfarin (with resultant increase in prothrombin time), antipyrine (l), diazepam (2), and chlordiazepoxide (3). These agents are known to require microsomal oxidation for elimination. In contrast, cimetidine was found to have no effect upon the elimination of lorazepam and oxazepam in humans (4,s); these benzodiazepines are known to be eliminated by glucuronidation. Animal studies have also demonstrated that cimetidine inhibits microsomal oxidative drug metabolism, both in vitro (6,7) and in vivo (7,8). Chlordiazepoxide (Librium; Roche Laboratories, Nutley, N.J.), a benzodiazepine sedative, is frequently used in the treatment of anxiety states, alcohol withdrawal, and peptic ulcer disease. Hence the simultaneous use of chlordiazepoxide and cimetidine would be a frequent occurrence. We have previously demonstrated that therapeutic doses of cimetidine taken for 1 wk impaired the clearance of chlordiazepoxide (3). We report studies to define the time-course of this inhibition, to assess whether tolerance to this inhibition occurs with continued cimetidine use, and finally to determine how rapidly the inhibitory effect is reversed.
Method Chlordiazepoxide disposition and elimination was studied in 7 healthy, nonsmoking subjects (5 males, 2 females), 22-43 yr old. Each had a normal history, physical examination, and laboratory profile (SMA-12, CBC). No subject had been taking other medications for at least 2 wk
before and throughout the study. Each subject gave written informed consent, and the study was approved by the
548
PATWARDHAN
GASTROENTEROLOGY
_ B.
CHLORDIAZEPOXIDE
A.
6ooO
ET AL.
CHLORDIAZEPOXIDE AFTER
CONTROLS
t
Vol. 81. No. 3
24
I
CIMETIDINE HOURS
Figure 1. Plasma concentration/time profiles of chlordiazepoxide and N-desmethylchlordiazepoxide in 7 normal subjects for the four phases of the study. The solid line depicts chlordiazepoxide decay and the dashed line, the accumulation of Ndesmethylchlordiazepoxide. Each point represents the mean f SEM of seven studies.
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1 40
I 50
1 60
TIME
Institutional jects.
Committee
Protocol
CHLODIAZEPOXIDE AFTER
for the Protection
I 0
I 10
STOPPING 40
HOURS
1 20
I 30
CIMETIDINE
1 40
I 50
J 60
(HOURS)
of Human
Sub-
for Study
Chlordiazepoxide disposition and elimination was studied on four separate occasions in all subjects in the following sequence: (a) baseline study (no pretreatment); (b) cimetidine, 1200 mg in 4 equally divided doses, was given 24 h before and throughout the 56 h of blood collection (acute study); (c) cimetidine, 1200 mg in similarly divided doses, was given for 30 days before and throughout the 56 h of blood collection (chronic study); and (d) two days after stopping cimetidine (recovery study). Chlordiazepoxide was prepared immediately before each study as a 5-mg/ml solution in normal saline and was given intravenously over 1 min into an antecubital vein at
a dose of 0.6 mg/kg. From an indwelling cannula placed in the opposite arm (kept patent with normal saline), blood samples were collected into heparinized tubes at 0, 5, 10, 15, 30, and 60 min and then at 2, 3, 4, 5, 6, 8, 12, 24, 32, 40, and 56 h after injection. Plasma levels of chlordiazepoxide and its first metabolite, IV-desmethylchlordiazepoxide, were measured by high-performance liquid chromatography (9), and plasma chlordiazepoxide binding was measured by equilibrium dialysis on plasma samples taken at zero time in each study (lo). Plasma chlordiazepoxide levels declined biexponentially with time, and the data from each subject were analyzed accordingly, after weighting by a coefficient of variation of 0.05, according to a two-compartmental open model and by a modified version of the least-squares iterative digital computer program-SAAM23 (ll),to the func-
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PATWARDHAN
550
GASTROENTEROLOGY
ET AL.
ELIMINATION
HALF-LIFE
tV2(ppours)
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20
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I
I
FREE CLEARANCE 25 r
0' CONTROL
1
24 HRS CIMETIDINE
I CONTROL
I
I
I
I
(ml/min/kg)
I 30 DAYS CIMETIDINE
30 DAYS CIMETIDINE
48 HRS AFTER STOPPING CIMETIDINE
Figure 2. Elimination half-life and free clearance in each subject during the four phases of the study. The horizontal bars represent mean values.
ies have shown that a single dose of cimetidine (60120 mg/kg) inhibits the elimination of aminopyrine in the rat (8); there was impaired diazepam elimination after 1000 mg of cimetidine in 5 divided doses in humans (13). We have now demonstrated that cimetidine inhibits the elimination of chlordiazepoxide after a l-day pretreatment, and this effect persists after a l-mo cimetidine treatment, indicating that tolerance does not develop to this inhibitory effect. This is similar to the effects of oral contraceptive steroids (14) and antabuse (15), but unlike the tolerance observed after alcohol (16,17). Furthermore, the cimetidine-induced inhibition was rapidly reversible (after withdrawing cimetidine for 48 h) implying absence of morphologic and structural hepatic damage by cimetidine. This supports studies with rat hepatic microsomes (6,7), which have demonstrated reversible spectral binding of cimetidine to microsomal suspensions in vitro. Chlordiazepoxide is almost exclusively eliminated after oxidative metabolism in the liver and has a relatively low extraction ratio and plasma clearance (20-30 ml/min). Its removal from plasma is thus de-
Vol. 81, No. 3
pendent on the functional capacity of mixed-function oxidase in the liver microsomes. As it is the free (unbound) drug that is available for metabolism, the free clearance of the drug best reflects the capacity of the liver to metabolize this low-clearance drug. In addition to measuring the elimination of chlordiazepoxide from plasma, we measured the first metabolite of chlordiazepoxide degradation and found that the generation and elimination of the pharmacologically active metabolite was also impaired by cimetidine. Although we have not measured subsequent degradative products of the metabolic sequence of chlordiazepoxide, these findings suggest that additional oxidative steps after N-demethylation of chlordiazepoxide may also be inhibited by cimetidine. These observations are consistent with findings recently reported for diazepam (2,5). The steady-state level of drug achieved (therapeutic drug level desired on chronic dosing) is determined by its plasma clearance while the time required to achieve and maintain this level is determined by its elimination half-life. Thus the coadministration of cimetidine and chlordiazepoxide (and presumably other drugs) would lead to higher steady-state levels, and it may be necessary either to reduce the dose of chlordiazepoxide, or to space dosing further apart-especially in the elderly and in patients with kidney and liver disease who may be more sensitive to the sedative effects of chlordiazepoxide and cimetidine per se. In summary, the present study demonstrates that the inhibitory effect is rapid in onset, that no tolerance develops, and that recovery is rapid upon cimetidine withdrawal.
References 1. Serlin MJ, Sibeon
2. 3.
4.
5.
6. 7.
8.
RB, Mossman S, et al. Cimetidine: interaction with oral anticoagulants in man. Lancet 1979;2:317-9. Klotz V, Reimann I. Delayed clearance of diazepam due to cimetidine. N Engl J Med 1980;302:1012-4. Desmond PV, Patwardhan RV, Schenker S, et al. Cimetidine impairs the elimination of chlordiazepoxide in man. Ann Intern Med 1980;93:266-8. Patwardhan RV, Yarborough GW, Desmond PV, et al. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 1980;79:912-6. Klotz LJ, Reimann I. Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam. Eur J Clin Pharmacol 1980;18:517-20. Rendic S, Sumjic V, Toso R, et al. Interaction of cimetidine with liver microsomes. Xenobiotica 1979;9:555-64. Pelkanen 0, Puureinen J. The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem Pharmacol 1980;29:3075-80. Desmond PV, Patwardhan RV, Parker R, et al. Effect of cimetidine and other antihistamines on the elimination of aminopyrine, phenacetin and caffeine. Life Sci 1979;28:1261-8.
September
1961
CIMETIDINE INHIBITION OF CHLORDIAZEPOXIDE
9. Peat MA, Finkle BS, Deyman ME. High pressure liquid chromatographic determination of chlordiazepoxide and its major metabolite in biological fluids. J Pharm Sci 1979;66:1467-6. 10.Johnson RF, Schenker S, Roberts RK, et al. Plasma binding of benzodiazepines in humans. J Pharm Sci 1979;66:1320-2. 11.Berman M, Weiss MF. SAAM Manual, Public Health Service Manual No. 1703.Washington, D.C.: U.S. Government Printing Office, 1966. 12.Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975;55:347-59. 13. Klotz U, Antilla V-J, Reimann J. Cimetidine/diazepam inter-
ELIMINATION
551
action (lett). Lancet 1979;2:699. 14. Patwardhan RV, Desmond PV, Johnson RF, et al. Impaired elimination of caffeine by oral contraceptive steroids. J Lab Clin Med 1980;95:693-6. 15. Lang M. Marselos M, Torronen R. Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. I. Mixedfunction oxygenase. Chem-Biol Interactions 1978;15:267-76. 16.Sellers EM, Holloway MR. Drug kinetics and alcohol ingestion. Clinical Pharmacokinet 1978;3:44&52. 17. Iber FL. Drug metabolism in heavy consumers of ethyl alcohol. Clin Pharmacol Ther 1977;22:735-42.