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. doi: 10.1007/s002280050545.


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.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Anti-Inflammatory Agents / pharmacokinetics*
  • Anti-Inflammatory Agents / urine
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Dapsone / pharmacokinetics*
  • Dapsone / urine
  • Female
  • HIV Protease Inhibitors / pharmacology*
  • Humans
  • Hydrocortisone / pharmacokinetics*
  • Hydrocortisone / urine
  • Hydroxylation
  • Indinavir / pharmacology
  • Kinetics
  • Leprostatic Agents / pharmacokinetics*
  • Leprostatic Agents / urine
  • Male
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Predictive Value of Tests
  • Ritonavir / pharmacology


  • Anti-Inflammatory Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • HIV Protease Inhibitors
  • Leprostatic Agents
  • Indinavir
  • Dapsone
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ritonavir
  • Hydrocortisone