Neither dapsone hydroxylation nor cortisol 6beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

Neither dapsone hydroxylation nor cortisol 6beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors.

Eur J Clin Pharmacol. 1998 Nov-Dec;54(9-10):741-7. Unique Identifier : AIDSLINE MED/99120453
Gass RJ; Gal J; Fogle PW; Detmar-Hanna D; Gerber JG; Department of Medicine, University of Colorado Health Sciences; Center, Denver 80262, USA.

Abstract: OBJECTIVE: This study examined the use of dapsone N-hydroxylation and cortisol 6beta-hydroxylation, well accepted in vivo probes of cytochrome P4503A4 (CYP3A4) activity, on defining the effect of three HIV protease inhibitors on CYP3A4 activity. METHODS: Subjects from University Hospital Infectious Disease Clinic about to be started on indinavir, and subjects from two clinical studies, one using ritonavir and the other using amprenavir, were recruited to participate in the study. Subjects received dapsone 100 mg p.o. followed by an 8-h urine collection for dapsone, dapsone N-hydroxylamine, cortisol, and 6beta-hydroxycortisol concentrations before HIV protease inhibitor administration, and 3 4 weeks into receiving HIV protease inhibitors. RESULTS: None of the HIV protease inhibitors demonstrated statistically significant alterations in dapsone recovery ratio and 6beta-hydroxycortisol/cortisol ratio. In fact, with ritonavir, the dapsone recovery ratio tended to increase rather than decrease, suggesting induction. These negative results were found despite evidence of CYP3A4 inhibition by these three HIV protease inhibitors via published drug-drug interactions with drugs that are substrates for CYP3A4. CONCLUSIONS: These in vivo assays used to probe CYP3A4 activity are suboptimal, most likely because of the presence of extrahepatic sites of metabolism for both dapsone and cortisol, and multiple CYP isozymes involved in dapsone N-hydroxylation.

Keywords: CLINICAL TRIAL JOURNAL ARTICLE Adult Anti-Inflammatory Agents, Steroidal/*DIAGNOSTIC USE/ *PHARMACOKINETICS/URINE Chromatography, High Pressure Liquid Cytochrome P-450/*ANTAGONISTS & INHIB Dapsone/*DIAGNOSTIC USE/*PHARMACOKINETICS/URINE Female Human Hydrocortisone/*DIAGNOSTIC USE/*PHARMACOKINETICS/URINE Hydroxylases/*ANTAGONISTS & INHIB Hydroxylation HIV Protease Inhibitors/*PHARMACOLOGY Indinavir/PHARMACOLOGY Kinetics Leprostatic Agents/*DIAGNOSTIC USE/*PHARMACOKINETICS/URINE Male Predictive Value of Tests Ritonavir/PHARMACOLOGY
990630
A9960938

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