In Vitro And In Vivo Effects Of The Arylamine Human Immunodeficiency Virus Protease Inhibitor 4r-(4 Alpha,5 Alpha,6 Beta,7 Beta)-1-[(3-(1-Imidazoylcarbamonyl)Phenyl) Methyl]-3-[(3-Aminophenyl)Methyl]Hexahydro-5,6-Dihydroxy-4,7-Bis (Phenylmethyl)-2h-1,3-Diazepin-2-One (Sd894) On Rat Hepatic Cytochrome P450 2b And 3a

The human immunodeficiency virus-1 protease inhibitor SD894 was evaluated as an inhibitor and inducer of cytochromes P450 (CYPs) in rats, After addition of 10 mu M SD894 and 2 mM NADPH to liver microsomes from dexamethasone-treated rats, a type ii spectrum appeared. Within 2 min, it was replaced by a type ill spectrum, with absorbance maxima at 426 and 456 nm, similar to those observed with alkylamines (SKF-525A) and arylamines (p-chloroaniline). Preincubation of microsomes from dexamethasone-treated rats with SD894 and NADPH resulted in a time-dependent inhibition of testosterone 6 beta-hydroxylation (CYP 3A1/2 activity), which was decreased to 25% of controls after 30 min, Testosterone 16 beta-hydroxylation (CYP 2B1/2 activity) was unaffected under these conditions. Testosterone 6 beta-hydroxylation rates in liver microsomes from pregnenolone 16 alpha-carbonitrile-treated rats incubated with 10 mu M SD894 and NADPH, washed, and reisolated by ultra centrifugation were reduced by 71%, whereas 16 beta-hydroxylation was unaffected by SD894. Immunoblots of liver microsomes from rats dosed iv with SD894 or ip with TAO displayed increased CYP 2B1 and CYP 3A1 levels, respectively, Testosterone 6 beta-hydroxylase activity in microsomes from TAO-treated rats was greater than controls, Preincubation of these microsomes with potassium ferricyanide produced an additional 50% increase, consistent with disruption of a metabolite-GYP complex. Microsomes from SD894-treated rats displayed a 3-fold increase in testosterone 16 beta-hydroxylation. Potassium ferricyanide preincubation did not increase activity. Thus, although SD894 appears to inhibit CYP in vitro in a manner typical of other amine-containing, mechanism-based inhibitors, in vivo induction by 10 mg/kg daily doses of SD894 affects a different isozyme than does inhibition. The mechanism of induction is unknown.