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

Objective: This study examined the use of dapsone N-hydroxylation and corti sol 6 beta-hydroxylation, well accepted in vivo probes of cytochrome P4503A 4 (CYP3A4) activity, on defining the effect of three HIV protease inhibitor s on CYP3A4 activity. Methods: Subjects from University Hospital Infectious Disease Clinic about to be started on indinavir, and subjects from two clinical studies, one usi ng 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 urin e collection for dapsone, dapsone N-hydroxylamine, cortisol, and 6 beta-hyd roxycortisol concentrations before HIV protease inhibitor administration, a nd 3-4 weeks into receiving HIV protease inhibitors. Results: None of the HIV protease inhibitors demonstrated statistically sig nificant alterations in dapsone recovery ratio and 6 beta-hydroxycortisol/c ortisol ratio. In fact, with ritonavir, the dapsone recovery ratio tended t o increase rather than decrease, suggesting induction. These negative resul ts were found despite evidence of CYP3A4 inhibition by these three HIV prot ease inhibitors via published drug-drug interactions with drugs that are su bstrates for CYP3A4. Conclusions: These in vivo assays used to probe CYP3A4 activity are subopti mal, most likely because of the presence of extrahepatic sites of metabolis m for both dapsone and cortisol, and multiple CYP isozymes involved in daps one N-hydroxylation.