PT  - JOURNAL ARTICLE
AU  - Mary F. Grubb
AU  - Sharon Diamond
AU  - David D. Christ
TI  - <em>In Vitro</em> and <em>In Vivo</em> Effects of the Arylamine Human Immunodeficiency Virus Protease Inhibitor 4<em>R</em>-(4α,5α,6β,7β)-1-[(3-(1-Imidazoylcarbamoyl)phenyl)methyl]-3-[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2<em>H</em>-1,3-diazepin-2-one (SD894) on Rat Hepatic Cytochrome P450 2B and 3A
DP  - 1997 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1424--1428
VI  - 25
IP  - 12
4099  - http://dmd.aspetjournals.org/content/25/12/1424.short
4100  - http://dmd.aspetjournals.org/content/25/12/1424.full
SO  - Drug Metab Dispos1997 Dec 01; 25
AB  - 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 μM 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 III 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 6β-hydroxylation (CYP 3A1/2 activity), which was decreased to 25% of controls after 30 min. Testosterone 16β-hydroxylation (CYP 2B1/2 activity) was unaffected under these conditions. Testosterone 6β-hydroxylation rates in liver microsomes from pregnenolone 16α-carbonitrile-treated rats incubated with 10 μM SD894 and NADPH, washed, and reisolated by ultracentrifugation were reduced by 71%, whereas 16β-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 6β-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-CYP complex. Microsomes from SD894-treated rats displayed a 3-fold increase in testosterone 16β-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. The American Society for Pharmacology and Experimental Therapeutics