Summary
In seven healthy male volunteers the effects of the pattern of dosing on the pharmacokinetics of diazepam have been studied. A cross-over design was employed that consisted of three parts: a single intravenous dose (0.1 mg/kg), and oral dosing (10 mg/day) for six days followed by an intravenous bolus (0.1 mg/kg) on the seventh day, followed by re-examination of a single intravenous dose after diazepam (D) and its major metabolite desmethyldiazepam (DD) had been completely eliminated. Plasma levels of D and DD were monitored by a specific, sensitive GLC-method. In younger patients (n=5, age 29 – 35 years) the elimination half-life, T1/2 (β), of D was 33.9±10.6 h (mean±S.D.) after the single dose. The control study gave an almost identical result (35.7±12.1). After subchronic dosage in all patients T1/2 (β) showed a modest but significant prolongation (paired t-test p<0.01) to 52.9±17.4 h. It was caused by a significant decrease (p=0.016) in total plasma clearance (\(\overline {\user1{Cl}} \)), from 26.0±10.8 ml/min to 18.2±7.0 ml/min. Older patients (age 43–60 years) showed the same phenomenon. Blood/plasma ratios remained constant indicating no change in protein binding. Biliary excretion of D was measured in five patients with a T-tube. Only negligible amounts (0.3–0.4%) of administered D were excreted within 3 days after subchronic dosage, which demonstrates a lack of enterohepatic cycling of D. After multiple administration of D, there was accumulation of DD to levels approximately five times higher than after a single dose. The possibility that the slower elimination of D after subchronic treatment might be caused by DD was also supported by experiments in dogs and rabbits. After pretreating rabbits with DD and maintaining a high DD plasma level, there was prolongation of T1/2 (β) from 2.7 h to 5.2 h, with a corresponding decrease of\(\overline {\user1{Cl}} \) from 101.6 ml/min to 23.4 ml/min. Similar results were obtained in dogs. It is concluded that the disposition of D is altered by subchronic use and may be regulated by the plasma DD concentration.
Similar content being viewed by others
References
Schwartz, M.A., Koechlin, B.A., Postma, E., Palmer, S., Krol, G.: Metabolism of diazepam in rat, dog, and man. J. Pharmacol. exp. Ther.149, 423–435 (1965)
de Silva, J.A.F., Koechlin, B.A. Bader, G.: Blood level distribution patterns of diazepam and its major metabolite in man. J. pharm. Sci.55, 692–702 (1966)
Randall, L.O., Scheckel, C.L., Banzinger, R.F.: Pharmacology of the metabolites of chlordiazepoxide and diazepam. Curr. ther. Res.7, 590–606 (1965)
Klot, U., Avant, G.R., Hoyumpa, A., Schenker, S., Wilkinson, G.R.: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J. clin. Invest.55, 347–359 (1975)
Nayak, R.K., Smith, R.D., Chamberlain, J.H., Polk, A., de Long, A.F., Herczeg, T., Chemburkar, P.B., Joslin, R.S., Reavey-Cantwell, N.H.: Methaqualone pharmacokinetics after single- and multiple dose administration in man. J. Pharmacokin. Biopharm.2, 107–121 (1974)
Doluisio. J.T., Dittert, L.W.: Influence of repetitive dosing of tetracyclines on biologic half-life in serum. Clin. Pharmacol. Ther.10, 690–701 (1969)
Eichelbaum, M., Ekbom, K., Bertilsson, L., Ringberger, V.A., Rane, A.: Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Europ. J. clin. Pharmacol.8, 337–341 (1975)
Berman, M., Weiss, M.F.: SAAM Manual. Laboratory of Theoretical Biology, Bethesda/Maryland: NIH (1974)
Riegelman, S., Loo, J.C.K., Rowland, M.: Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit the properties of a single compartment. J. pharm. Sci.57, 117–123 (1968)
Jusko, W.J., Gibaldi, M.: Effects of change in elimination on various parameters of the two-compartment open model. J. pharm. Sci.61, 1270–1273 (1972)
van der Kleijn, E., van Rossum, J.M., Muskens, E.I.J.M., Rinjntjes, N.V.M.: Pharmacokinetics of diazepam in dogs, mice and humans. Acta pharmacol. (Kbh.)29, (Suppl. 3), 109–127 (1971)
van der Kleijn, E.: Pharmacokinetics of distribution and metabolism of ataractic drugs and evaluation of the site of antianxiety activity. Ann. N.Y. Acad. Sci.179, 115–125 (1971)
Berlin, A., Siwers, B., Agurell, S., Hiort, A., Sjöqvist, F., Ström, S.: Determination of bioavailability of diazepam in various formulations from steady state plasma concentration data. Clin. Pharmacol. Ther.13, 733–744 (1972)
Kaplan, S.A., Jack, M.L., Alexander, K., Weinfeld, R.E.: Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administrations. J. pharm. Sci.62, 1789–1796 (1973)
Mahon, W., Inaba, T., Umeda, T., Tsutsumi, E.: The biliary elimination of benzodiazepines in man: Abstract 118, 6th International Concress of Pharmacology, Helsinki 1975
Klotz, U., Antonin, K.H., Bieck, P.R.: Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig, and rat. J. Pharmacol. exp. Ther. in press (1976)
Arnold, K., Gerber, N.: The rate of decline of diphenylhydantoin in human plasma. Clin. Pharmacol. Ther.11, 121–134 (1970)
Marcucci, F., Fanelli, R., Mussini, E., Garratini, S.: The metabolism of diazepam by liver microsomal enzymes of rats and mice. Europ. J. Pharmacol.7, 307–313 (1969)
Orme, M., Breckenridge, A., Brooks, R.V.: Interaction of benzodiazepines with warfarin. Brit. med. J.1972 III, 611–614
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Klotz, U., Antonin, K.H. & Bieck, P.R. Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur J Clin Pharmacol 10, 121–126 (1976). https://doi.org/10.1007/BF00609470
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00609470