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. 1994 Jul;38(1):23–31. doi: 10.1111/j.1365-2125.1994.tb04317.x

Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine.

L L von Moltke 1, D J Greenblatt 1, M M Cotreau-Bibbo 1, J S Harmatz 1, R I Shader 1
PMCID: PMC1364833  PMID: 7946933

Abstract

1. The biotransformation of the triazolobenzodiazepine alprazolam (ALP) to its hydroxylated metabolites (4-OH-ALP and alpha-OH-ALP) was evaluated in human, monkey, rat, and mouse liver microsomes. 2. In all species 4-OH-ALP was the principal metabolite, accounting for 84% of clearance in human microsomes compared with 16% for alpha-OH-ALP. 3. Among the serotonin-specific reuptake inhibitors fluoxetine (FLU) and sertraline (SERT), and their respective demethylated metabolites norfluoxetine (NOR) and desmethylsertraline (DES), NOR was the most potent inhibitor (mean Ki for 4-OH-ALP formation in humans: 11 microM), FLU the weakest (Ki = 83 microM), with SERT and DES falling in between (Ki = 24 and 20 microM). 4. The in vitro data predict 29% inhibition of ALP clearance at mean FLU and NOR plasma concentrations of 77 ng ml-1 and 72 ng ml-1, respectively, after correction for liver:water partition ratios in the range of 12-14. The observed mean degree of inhibition in a previous in vivo study was 21%. 5. Ketoconazole was a potent inhibitor of ALP metabolism in vitro (Ki = 0.046 microM), suggesting that ALP hydroxylation is mediated by the cytochrome P450-3A sub-family. Quinidine was a weak inhibitor (Ki = 626 microM).

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Selected References

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  1. Back D. J., Stevenson P., Tjia J. F. Comparative effects of two antimycotic agents, ketoconazole and terbinafine on the metabolism of tolbutamide, ethinyloestradiol, cyclosporin and ethoxycoumarin by human liver microsomes in vitro. Br J Clin Pharmacol. 1989 Aug;28(2):166–170. doi: 10.1111/j.1365-2125.1989.tb05410.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Badcock N. R., Bartholomeusz F. D., Frewin D. B., Sansom L. N., Reid J. G. The pharmacokinetics of ketoconazole after chronic administration in adults. Eur J Clin Pharmacol. 1987;33(5):531–534. doi: 10.1007/BF00544251. [DOI] [PubMed] [Google Scholar]
  3. Banks W. R., Yamakita H., Digenis G. A. Metabolism and distribution of 1-[14C]alprazolam in rats. J Pharm Sci. 1992 Aug;81(8):797–801. doi: 10.1002/jps.2600810815. [DOI] [PubMed] [Google Scholar]
  4. Beaune P. H., Guengerich F. P. Human drug metabolism in vitro. Pharmacol Ther. 1988;37(2):193–211. doi: 10.1016/0163-7258(88)90025-3. [DOI] [PubMed] [Google Scholar]
  5. Benfield P., Heel R. C., Lewis S. P. Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs. 1986 Dec;32(6):481–508. doi: 10.2165/00003495-198632060-00002. [DOI] [PubMed] [Google Scholar]
  6. Bickett D. J., MacKenzie P. I., Veronese M. E., Miners J. O. In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci. 1993 Aug;14(8):292–294. doi: 10.1016/0165-6147(93)90043-j. [DOI] [PubMed] [Google Scholar]
  7. Bogeyevitch M. A., Gillam E. M., Reilly P. E., Winzor D. J. Physical partitioning as the major source of metoprolol uptake by hepatic microsomes. Biochem Pharmacol. 1987 Dec 1;36(23):4167–4168. doi: 10.1016/0006-2952(87)90576-4. [DOI] [PubMed] [Google Scholar]
  8. Brosen K. Recent developments in hepatic drug oxidation. Implications for clinical pharmacokinetics. Clin Pharmacokinet. 1990 Mar;18(3):220–239. doi: 10.2165/00003088-199018030-00004. [DOI] [PubMed] [Google Scholar]
  9. Brøsen K., Skjelbo E. Fluoxetine and norfluoxetine are potent inhibitors of P450IID6--the source of the sparteine/debrisoquine oxidation polymorphism. Br J Clin Pharmacol. 1991 Jul;32(1):136–137. doi: 10.1111/j.1365-2125.1991.tb05630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cholerton S., Daly A. K., Idle J. R. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci. 1992 Dec;13(12):434–439. doi: 10.1016/0165-6147(92)90140-2. [DOI] [PubMed] [Google Scholar]
  11. Chou C. H., Evans A. M., Fornasini G., Rowland M. Relationship between lipophilicity and hepatic dispersion and distribution for a homologous series of barbiturates in the isolated perfused in situ rat liver. Drug Metab Dispos. 1993 Sep-Oct;21(5):933–938. [PubMed] [Google Scholar]
  12. Ciraulo D. A., Antal E. J., Smith R. B., Olson D. R., Goldberg D. A., Rand E. H., Raskin R. B., Phillips J. P., Shader R. I., Greenblatt D. J. The relationship of alprazolam dose to steady-state plasma concentrations. J Clin Psychopharmacol. 1990 Feb;10(1):27–32. doi: 10.1097/00004714-199002000-00005. [DOI] [PubMed] [Google Scholar]
  13. Ciraulo D. A., Shader R. I. Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics. J Clin Psychopharmacol. 1990 Feb;10(1):48–50. doi: 10.1097/00004714-199002000-00009. [DOI] [PubMed] [Google Scholar]
  14. Crewe H. K., Lennard M. S., Tucker G. T., Woods F. R., Haddock R. E. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol. 1992 Sep;34(3):262–265. doi: 10.1111/j.1365-2125.1992.tb04134.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dawson G. W., Jue S. G., Brogden R. N. Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drugs. 1984 Feb;27(2):132–147. doi: 10.2165/00003495-198427020-00002. [DOI] [PubMed] [Google Scholar]
  16. Fawcett J. A., Kravitz H. M. Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action. Pharmacotherapy. 1982 Sep-Oct;2(5):243–254. doi: 10.1002/j.1875-9114.1982.tb03191.x. [DOI] [PubMed] [Google Scholar]
  17. Fraser A. D., Isner A. F., Perry R. A. Distribution of trimipramine and its major metabolites in a fatal overdose case. J Anal Toxicol. 1987 Jul-Aug;11(4):168–170. doi: 10.1093/jat/11.4.168. [DOI] [PubMed] [Google Scholar]
  18. Gascon M. P., Dayer P. In vitro forecasting of drugs which may interfere with the biotransformation of midazolam. Eur J Clin Pharmacol. 1991;41(6):573–578. doi: 10.1007/BF00314987. [DOI] [PubMed] [Google Scholar]
  19. Gonzalez F. J. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci. 1992 Sep;13(9):346–352. doi: 10.1016/0165-6147(92)90107-h. [DOI] [PubMed] [Google Scholar]
  20. Gonzalez F. J. In vitro systems for prediction of rates of drug clearance and drug interactions. Anesthesiology. 1992 Sep;77(3):413–415. doi: 10.1097/00000542-199209000-00001. [DOI] [PubMed] [Google Scholar]
  21. Greenblatt D. J., Abernethy D. R., Divoll M. Kinetics of low-dose intravenous antipyrine: use of liquid chromatography. Int J Clin Pharmacol Ther Toxicol. 1983 Feb;21(2):51–55. [PubMed] [Google Scholar]
  22. Greenblatt D. J., Harmatz J. S., Shader R. I. Plasma alprazolam concentrations. Relation to efficacy and side effects in the treatment of panic disorder. Arch Gen Psychiatry. 1993 Sep;50(9):715–722. doi: 10.1001/archpsyc.1993.01820210049006. [DOI] [PubMed] [Google Scholar]
  23. Greenblatt D. J., Preskorn S. H., Cotreau M. M., Horst W. D., Harmatz J. S. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther. 1992 Nov;52(5):479–486. doi: 10.1038/clpt.1992.175. [DOI] [PubMed] [Google Scholar]
  24. Greenblatt D. J., Wright C. E. Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clin Pharmacokinet. 1993 Jun;24(6):453–471. doi: 10.2165/00003088-199324060-00003. [DOI] [PubMed] [Google Scholar]
  25. Greenblatt D. J., von Moltke L. L., Harmatz J. S., Ciraulo D. A., Shader R. I. Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications. J Clin Psychiatry. 1993 Oct;54 (Suppl):4–14. [PubMed] [Google Scholar]
  26. Guengerich F. P. Human cytochrome P-450 enzymes. Life Sci. 1992;50(20):1471–1478. doi: 10.1016/0024-3205(92)90136-d. [DOI] [PubMed] [Google Scholar]
  27. Guengerich F. P., Müller-Enoch D., Blair I. A. Oxidation of quinidine by human liver cytochrome P-450. Mol Pharmacol. 1986 Sep;30(3):287–295. [PubMed] [Google Scholar]
  28. Honig P. K., Wortham D. C., Zamani K., Conner D. P., Mullin J. C., Cantilena L. R. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA. 1993 Mar 24;269(12):1513–1518. [PubMed] [Google Scholar]
  29. Kroemer H. K., Echizen H., Heidemann H., Eichelbaum M. Predictability of the in vivo metabolism of verapamil from in vitro data: contribution of individual metabolic pathways and stereoselective aspects. J Pharmacol Exp Ther. 1992 Mar;260(3):1052–1057. [PubMed] [Google Scholar]
  30. Kronbach T., Mathys D., Umeno M., Gonzalez F. J., Meyer U. A. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol. 1989 Jul;36(1):89–96. [PubMed] [Google Scholar]
  31. Lasher T. A., Fleishaker J. C., Steenwyk R. C., Antal E. J. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology (Berl) 1991;104(3):323–327. doi: 10.1007/BF02246031. [DOI] [PubMed] [Google Scholar]
  32. Murdoch D., McTavish D. Sertraline. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depression and obsessive-compulsive disorder. Drugs. 1992 Oct;44(4):604–624. doi: 10.2165/00003495-199244040-00007. [DOI] [PubMed] [Google Scholar]
  33. Murray M. P450 enzymes. Inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet. 1992 Aug;23(2):132–146. doi: 10.2165/00003088-199223020-00005. [DOI] [PubMed] [Google Scholar]
  34. Otton S. V., Crewe H. K., Lennard M. S., Tucker G. T., Woods H. F. Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J Pharmacol Exp Ther. 1988 Oct;247(1):242–247. [PubMed] [Google Scholar]
  35. Otton S. V., Wu D., Joffe R. T., Cheung S. W., Sellers E. M. Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther. 1993 Apr;53(4):401–409. doi: 10.1038/clpt.1993.43. [DOI] [PubMed] [Google Scholar]
  36. Peck C. C., Temple R., Collins J. M. Understanding consequences of concurrent therapies. JAMA. 1993 Mar 24;269(12):1550–1552. [PubMed] [Google Scholar]
  37. Resetar A., Minick D., Spector T. Glucuronidation of 3'-azido-3'-deoxythymidine catalyzed by human liver UDP-glucuronosyltransferase. Significance of nucleoside hydrophobicity and inhibition by xenobiotics. Biochem Pharmacol. 1991 Jul 15;42(3):559–568. doi: 10.1016/0006-2952(91)90319-z. [DOI] [PubMed] [Google Scholar]
  38. Scavone J. M., Friedman H., Greenblatt D. J., Shader R. I. Effect of age, body composition, and lipid solubility on benzodiazepine tissue distribution in rats. Arzneimittelforschung. 1987 Jan;37(1):2–6. [PubMed] [Google Scholar]
  39. Schmith V. D., Cox S. R., Zemaitis M. A., Kroboth P. D. New high-performance liquid chromatographic method for the determination of alprazolam and its metabolites in serum: instability of 4-hydroxyalprazolam. J Chromatogr. 1991 Jul 17;568(1):253–260. doi: 10.1016/0378-4347(91)80361-f. [DOI] [PubMed] [Google Scholar]
  40. Skjelbo E., Brøsen K. Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol. 1992 Sep;34(3):256–261. doi: 10.1111/j.1365-2125.1992.tb04133.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Smith R. B., Kroboth P. D. Influence of dosing regimen on alprazolam and metabolite serum concentrations and tolerance to sedative and psychomotor effects. Psychopharmacology (Berl) 1987;93(1):105–112. doi: 10.1007/BF02439595. [DOI] [PubMed] [Google Scholar]
  42. Sommi R. W., Crismon M. L., Bowden C. L. Fluoxetine: a serotonin-specific, second-generation antidepressant. Pharmacotherapy. 1987 Jan-Feb;7(1):1–15. doi: 10.1002/j.1875-9114.1987.tb03496.x. [DOI] [PubMed] [Google Scholar]
  43. Swinney D. C. Progesterone metabolism in hepatic microsomes. Effect of the cytochrome P-450 inhibitor, ketoconazole, and the NADPH 5 alpha-reductase inhibitor, 4-MA, upon the metabolic profile in human, monkey, dog, and rat. Drug Metab Dispos. 1990 Nov-Dec;18(6):859–865. [PubMed] [Google Scholar]
  44. Tsuru M., Erickson R. R., Holtzman J. L. The metabolism of phenytoin by isolated hepatocytes and hepatic microsomes from male rats. J Pharmacol Exp Ther. 1982 Sep;222(3):658–661. [PubMed] [Google Scholar]
  45. Tucker G. T. The rational selection of drug interaction studies: implications of recent advances in drug metabolism. Int J Clin Pharmacol Ther Toxicol. 1992 Nov;30(11):550–553. [PubMed] [Google Scholar]
  46. Watkins P. B. Role of cytochromes P450 in drug metabolism and hepatotoxicity. Semin Liver Dis. 1990 Nov;10(4):235–250. doi: 10.1055/s-2008-1040480. [DOI] [PubMed] [Google Scholar]
  47. Wrighton S. A., Stevens J. C. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992;22(1):1–21. doi: 10.3109/10408449209145319. [DOI] [PubMed] [Google Scholar]
  48. van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin Pharmacokinet. 1993 Mar;24(3):203–220. doi: 10.2165/00003088-199324030-00003. [DOI] [PubMed] [Google Scholar]
  49. von Bahr C., Spina E., Birgersson C., Ericsson O., Göransson M., Henthorn T., Sjöqvist F. Inhibition of desmethylimipramine 2-hydroxylation by drugs in human liver microsomes. Biochem Pharmacol. 1985 Jul 15;34(14):2501–2505. doi: 10.1016/0006-2952(85)90533-7. [DOI] [PubMed] [Google Scholar]
  50. von Moltke L. L., Greenblatt D. J., Cotreau-Bibbo M. M., Duan S. X., Harmatz J. S., Shader R. I. Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J Pharmacol Exp Ther. 1994 Mar;268(3):1278–1283. [PubMed] [Google Scholar]
  51. von Moltke L. L., Greenblatt D. J., Harmatz J. S., Shader R. I. Alprazolam metabolism in vitro: studies of human, monkey, mouse, and rat liver microsomes. Pharmacology. 1993 Oct;47(4):268–276. doi: 10.1159/000139107. [DOI] [PubMed] [Google Scholar]
  52. von Moltke L. L., Manis M., Harmatz J. S., Poorman R., Greenblatt D. J. Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid. Biopharm Drug Dispos. 1993 Mar;14(2):119–130. doi: 10.1002/bdd.2510140204. [DOI] [PubMed] [Google Scholar]

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