Evidence that famciclovir (BRL 42810) and its associated metabolites do not inhibit the 6 beta-hydroxylation of testosterone in human liver microsomes.

Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir with potential use in the treatment of infections caused by the herpes family of viruses. The major pathway of metabolism of famciclovir is deacetylation to BRL 42359 followed by oxidation to penciclovir. It is possible that famciclovir may be coadministered with cyclosporin A to combat viral infections induced by immunosuppression in organ transplant and bone marrow transplant patients. As a result, information is required on possible interactions between the cytochrome P-450 3A substrate cyclosporin A and famciclovir and its metabolites in humans. In order to probe cytochrome P-450 3A activity, testosterone 6 beta-hydroxylation in two human liver microsomal preparations was measured. Nicardipine and ketoconazole, two drugs with known inhibitory interactions with cyclosporin A, were used as positive controls. Profiles of 6 beta-hydroxytestosterone production showed no inhibition effected by famciclovir, penciclovir, or BRL 42359 when marked inhibition was observed in incubations containing nicardipine, nifedipine, or ketoconazole. Further incubations of [14C]BRL 42359 with human liver cytosol and microsomes indicated that BRL 42359 is oxidized to penciclovir in cytosol but not in microsomes and that this reaction was not dependent on the presence of NADPH. Because P-450 resides mainly in the microsomal fraction and is dependent on the presence of cofactors for catalytic activity, it seems that this oxidation is not catalyzed by cytochrome P-450.(ABSTRACT TRUNCATED AT 250 WORDS)