Summary
Hydroxylated metabolites of diazepam can be conjugated and are therefore generally thought not to affect the metabolism of diazepam. Liver microsomes, obtained from phenobarbital-pretreated rats, showed an inhibition of diazepam (10−5 M) metabolism by desmethyldiazepam as well as by N-methyloxazepam or oxazepam (5 × 10−5 M). In a single-pass perfusion of the rat liver an inhibition of diazepam disposition by exogenously administered desmethyldiazepam and by hydroxylated diazepam metabolites was also demonstrated. No oxazepam glucuronides were found after oxazepam infusion. However, infusion with N-methyloxazepam resulted in large amounts of oxazepam-glucuronides.
The results indicate that administration of N-demethylated as well as hydroxylated metabolites may result in inhibition of the metabolism of their precursor. If hydroxylated metabolites are formed in situ they become more easily conjugated in comparison with administered hydroxylated metabolites and are therefore less effective as inhibitor.
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References
Bellantuono C., Reggi V., Tognoni G. and Garattini S. (1980): Benzodiazepines: Clinical pharmacology and therapeutic use. Drugs,19, 195–219.
Mandelli M., Tognoni G. and Garattini S. (1978): Clinical pharmacokinetics of diazepam. Clin. Pharmacokin.,3, 72–91.
Klotz U. (1978): Klinische Pharmakokinetik von Diazepam und seinen biologisch aktiven Metaboliten. Klin. Wochenschr.,56, 895–904.
Marcucci R., Fanelli R., Mussini E. and Garattini S. (1969): The metabolism of diazepam by liver microsomal enzymes of rats and mice. Eur. J. Pharmacol.,7, 307–313.
Igari Y., Sugiyama Y., Sawada Y., Iga T. and Hanano M. (1982): Tissue distribution of14C-diazepam and its metabolites in rats. Drug Metab. Disp.,10, 676–679.
Marcucci F., Fanelli R., Mussini E. and Garattini S. (1970): Effect of phenobarbital on thein vitro metabolism of diazepam in several animal species. Biochem. Pharmacol.,19, 1771–1776.
Klotz U. and Reimann I. (1981): Clearance of diazepam can be impaired by its major metabolite desmethyldiazepam. Eur. J. Clin. Pharmacol.,21, 161–163.
Klotz U., Antonin K.H. and Bieck P.R. (1976): Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur. J. Clin. Pharmacol.,10, 121–126.
Bast A., Scheefhals L.W.C. and Noordhoek J. (1982): Dose-dependent kinetics of aminopyrine metabolism in the rat caused by product inhibition and determined by capillary GLC. Pharmacology,25, 130–137.
Labout J.J.M., Thijssen C.T., Keijser G.G.J., and Hespe W. (1982): Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man. Eur. J. Clin. Pharmacol.,21, 343–350.
Levy G. and Ashley J.J. (1973): Effect of an inhibitor of glucuronide formation on elimination kinetics, of diphenylhydantoin in rats. J. Pharmaceut. Sci.,62, 161–162.
Von Bahr C. and Bertilsson L. (1971): Hydroxylation and subsequent glucuronide conjugation of desmethylimipramine in rat liver microsomes. Xenobiotica,1, 205–212.
Bast A. and Noordhoek J. (1980): Calculation of competitive inhibition of substrate binding to cytochrome P-450 illustrated by the interaction of d, 1-propranolol with d, 1-hexobarbital. Biochem. Pharmacol.,29, 747–751.
Bast A. and Noordhoek J. (1981): Evaluation and comparison of colorimetric, radiometric and high performance liquid chromatographic assays for aminopyrine-N-demethylation by rat liver microsomes. J. Pharm. Pharmacol.,33, 14–18.
Bertagni P., Marcucci F., Mussini E. and Garattini S. (1972): Biliary excretion of conjugated hydroxyl benzodiazepines after administration of several benzodiazepines to rats, guinea pigs, and mice. J. Pharmaceut. Sci.,61, 965–966.
Inaba T., Tsutsumi E., Mahon W.A. and Kalow W. (1974): Biliary excretion of diazepam in the rat. Drug Metab. Disp.,2, 429–432.
Vree T.B., Baars A.M., Hekster Y.A., Van der Kleijn E. and O’Reilly W.J. (1979): Simultaneous determinations of diazepam and its metabolites N-desmethyldiazepam, oxydiazepam and oxazepam in plasma and urine of man and dog by means of high-performance liquid chromatography. J. Chromat.,162, 605–614.
Savenije-Chapel E.M., Bast A. and Noordhoek J. (1983): Interaction of uridine 5′-diphosphoglucuronic acid (UDPGA) with cytochrome P-450. J. Pharm. Pharmacol.,35, 522–523.
Bast A. and Noordhoek J. (1981): Product inhibition during the hepatic microsomal N-demethylation of aminopyrine in the rat. Biochem. Pharmacol.,30, 19–24.
Lennard M.S., Tucker G.T. and Woods H.F. (1978): Dose-, time- and sex-dependent metabolism of lignocaine in the isolated perfused rat liver. Abstracts 7th International Congress of Pharmacology. Pergamon Press, Oxford, p. 836, abstract 2587.
Konishi M., Agoh T., Sato T., Konaka R. and Mori Y. (1980): Metabolism and disposition of peptido-aminobenzophenone (2-0-chlorobenzoyl-4-chloro-N-methyl-N’-glycylglycinanilide) and its major benzodiazepine metabolites in dogs. Drug Metab. Disp.,8, 253–259.
Von Bahr C. and Orrenius S. (1971): Spectral studies on the interaction of imipramine and some of its oxidized metabolites with rat liver microsomes. Xenobiotica,1, 69–78.
Ashley J.J. and Levy G. (1972): Inhibition of diphenyl-hydantoin elimination by its major metabolite. Res. Comm. Chem. Path. Pharmacol.,4, 297–306.
DePierre J.W., Moron M.S., Johannesen K.A.M. and Ernster L. (1975): A reliable, sensitive and convenient radioactive assay for benzpyrene monooxygenase. Anal. Biochem.,63, 470–484.
Rendic S. and Kajfez F. (1982): Stereochemical characterization of interactions of chiral 1,4-benzodiazepine-2-ones with liver microsomes. Eur. J. Drug Metab. Pharmacokin.,7, 137–146.
Abernethy D.R. and Greenblatt D.J. (1981): Effects of desmethyl-diazepam on diazepam kinetics: A study of effects of a metabolite on parent drug disposition. Clin. Pharmacol. Ther.,29, 757–761.
Bock K.W. (1978): Increase of liver microsomal benzo(a)pyrene monooxygenase activity by subsequent glucuronidation. Naunyn-Schmiedeberg’s Arch. Pharmacol,304, 77–79.
Fahl W.E., Shen A.L. and Jefcoate C.R. (1978): UDP-glucuronosyl transferase and the conjugation of benzo(a)pyrene metabolites t o DNA. Biochem. Biophys. Res. Comm.,85, 891–899.
Groothuis G. (1982): Acinar heterogeneity of hepatocytes in transport functions. Thesis, State University of Groningen.
Bass L. (1981): Functional zones in the liver. Gastroenterology,81, 976–977.
Garattini S., Marcucci F. and Mussini E. (1972): Benzodiazepine metabolismin vitro. Drug Metab. Rev.,1, 291–309.
Berte F., Benzi G., Manzo L. and Hokari S. (1968): Investigation on tissue distribution and metabolism of oxazepam in pregnant guinea-pig and rat. Arch. int. Pharmacodyn.,173, 377–381.
Conway J.G., Kauffman F.C., Ji S. and Thurman R.G. (1982): Rates of sulfation and glucuronidation of 7-hydroxycoumarin in periportal and pericentral regions of the liver lobule. Mol. Pharmacol.,22, 509–516.
Schwartz M.A., Koechlin B.A., Postma E., Palmer S. and Krol G. (1965): Metabolism of diazepam in rat, dog, and man. J. Pharmacol. Exp. Then,149, 423–435.
Lesca P., Beaune P. and Monsarrat B. (1981): Ellipticines and human liver microsomes: Spectral interaction with cytochrome P-450 and hydroxylation. Inhibition of aryl hydrocarbon metabolism and mutagenicity. Chem. Biol. Interact.,36, 299–309.
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Savenije-Chapel, E.M., Bast, A. & Noordhoek, J. Inhibition of diazepam metabolism in microsomal-and perfused liver preparations of the rat by desmethyldiazepam, N-methyloxazepam and oxazepam. European Journal of Drug Metabolism and Pharmacokinetics 10, 15–20 (1985). https://doi.org/10.1007/BF03189692
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DOI: https://doi.org/10.1007/BF03189692