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

225 Citations (Scopus)

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
StatePublished - Feb 1998
Externally publishedYes

Fingerprint

Ritonavir
Hydroxylation
Protease Inhibitors
Cytochrome P-450 Enzyme System
Nelfinavir
Saquinavir
Indinavir
Chlorzoxazone
Mephenytoin
Triazolam
Phenacetin
Dextromethorphan
Tolbutamide
Desipramine
Ketoconazole
Liver Microsomes
Cytochromes
Drug Interactions
Human Activities
Antiviral Agents

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Von Moltke, L. L., Greenblatt, D. J., Grassi, J. M., Granda, B. W., Duan, S. X., Fogelman, S. M., ... 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.

Protease inhibitors as inhibitors of human cytochromes P450 : High risk associated with ritonavir. / Von Moltke, Lisa L.; Greenblatt, David J.; Grassi, Jeffrey M.; Granda, Brian W.; Duan, Su Xiang; Fogelman, Steven M.; Daily, Johanna P.; Harmatz, Jerold S.; Shader, Richard I.

In: Journal of Clinical Pharmacology, Vol. 38, No. 2, 02.1998, p. 106-111.

Research output: Contribution to journalArticle

Von Moltke, LL, Greenblatt, DJ, Grassi, JM, Granda, BW, Duan, SX, Fogelman, SM, Daily, JP, Harmatz, JS & Shader, RI 1998, 'Protease inhibitors as inhibitors of human cytochromes P450: High risk associated with ritonavir', Journal of Clinical Pharmacology, vol. 38, no. 2, pp. 106-111.
Von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM et al. Protease inhibitors as inhibitors of human cytochromes P450: High risk associated with ritonavir. Journal of Clinical Pharmacology. 1998 Feb;38(2):106-111.
Von Moltke, Lisa L. ; Greenblatt, David J. ; Grassi, Jeffrey M. ; Granda, Brian W. ; Duan, Su Xiang ; Fogelman, Steven M. ; Daily, Johanna P. ; Harmatz, Jerold S. ; Shader, Richard I. / Protease inhibitors as inhibitors of human cytochromes P450 : High risk associated with ritonavir. In: Journal of Clinical Pharmacology. 1998 ; Vol. 38, No. 2. pp. 106-111.
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