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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.
Drug Metab Dispos. 1997 Dec; 25(12):1424-8.DM

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.

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Authors+Show Affiliations

Grubb MF
Drug Metabolism and Pharmacokinetics Section, The DuPont Merck Pharmaceutical Company, Newark, DE 19714, USA.
Diamond S
No affiliation info available
Christ DD
No affiliation info available

MeSH

AnimalsAryl Hydrocarbon HydroxylasesAzepinesCytochrome P-450 CYP2B1Cytochrome P-450 CYP3ACytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemEnzyme InductionHIV Protease InhibitorsImidazolesMaleMicrosomes, LiverOxidoreductases, N-DemethylatingRatsSpectrophotometryTime Factors

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9394033

Citation

Grubb, M F., et al. "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." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 25, no. 12, 1997, pp. 1424-8.
Grubb MF, Diamond S, Christ DD. 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. Drug Metab Dispos. 1997;25(12):1424-8.
Grubb, M. F., Diamond, S., & Christ, D. D. (1997). 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. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 25(12), 1424-8.
Grubb MF, Diamond S, Christ DD. 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. Drug Metab Dispos. 1997;25(12):1424-8. PubMed PMID: 9394033.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Grubb,M F, AU - Diamond,S, AU - Christ,D D, PY - 1998/1/31/pubmed PY - 1998/1/31/medline PY - 1998/1/31/entrez SP - 1424 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 25 IS - 12 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/9394033/In_vitro_and_in_vivo_effects_of_the_arylamine_human_immunodeficiency_virus_protease_inhibitor_4R__4alpha5alpha6beta_7beta__1_[_3__1_imidazoylcarbamoyl_phenyl_methyl]_3_[_3_aminophenyl_m_ethyl]hexahydro_56_dihydroxy_47_bis_phenylmethyl__2H_1_3_diazepin_2_one__SD894__on_rat_hepatic_cytochrome_P450_2B_and_3A_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9394033 DB - PRIME DP - Unbound Medicine ER -