Protease inhibitors as inhibitors of human cytochromes P450: High risk associated with ritonavir

Lisa L. Von Moltke, David J. Greenblatt, Jeffrey M. Grassi, Brian W. Granda, Su Xiang Duan, Steven M. Fogelman, Johanna P. Daily, Jerold S. Harmatz, Richard I. Shader

Research output: Contribution to journalArticle

228 Scopus citations

Abstract

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450-3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450-2C9 (tolbutamide hydroxylation), -2C19 (S-mephenytoin hydroxylation), and -2D6 (dextromethorphan O-demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450-1A2 (phenacetin O-deethylation) or -2E1 (chlorzoxazone hydroxylation). Thus among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.

Original languageEnglish (US)
Pages (from-to)106-111
Number of pages6
JournalJournal of Clinical Pharmacology
Volume38
Issue number2
DOIs
StatePublished - Feb 1998
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Von Moltke, L. L., Greenblatt, D. J., Grassi, J. M., Granda, B. W., Duan, S. X., Fogelman, S. M., Daily, J. P., Harmatz, J. S., & Shader, R. I. (1998). Protease inhibitors as inhibitors of human cytochromes P450: High risk associated with ritonavir. Journal of Clinical Pharmacology, 38(2), 106-111. https://doi.org/10.1002/j.1552-4604.1998.tb04398.x