title: In vitro and in vivo effects of the arylamine human immunodeficiency virus protease inhibitor 4R-(4alpha,5alpha,6beta, 7beta)-1-[(3-(1-imidazoylcarbamoyl)phenyl)methyl]-3-[(3-aminophenyl)m ethyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1, 3-diazepin-2-one (SD894) on rat hepatic cytochrome P450 2B and 3A.
abstract: 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 microM 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 6beta-hydroxylation (CYP 3A1/2 activity), which was decreased to 25% of controls after 30 min. Testosterone 16beta-hydroxylation (CYP 2B1/2 activity) was unaffected under these conditions. Testosterone 6beta-hydroxylation rates in liver microsomes from pregnenolone 16alpha-carbonitrile-treated rats incubated with 10 microM SD894 and NADPH, washed, and reisolated by ultracentrifugation were reduced by 71%, whereas 16beta-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 6beta-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 16beta-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.
authors.affiliation: Drug Metabolism and Pharmacokinetics Section, The DuPont Merck Pharmaceutical Company, Newark, DE 19714, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Grubb
authors.forename: S
authors.initials: S
authors.lastname: Diamond
authors.forename: D D
authors.initials: DD
authors.lastname: Christ
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001381:Azepines / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D013053:Spectrophotometry; D013997:Time Factors
chemical_list: D001381:Azepines; D065607:Cytochrome P-450 Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D007093:Imidazoles; C109843:SD 894; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating