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Titolo:
REGIOSELECTIVE BIOTRANSFORMATION OF MIDAZOLAM BY MEMBERS OF THE HUMANCYTOCHROME-P450-3A (CYP3A) SUBFAMILY
Autore:
GORSKI JC; HALL SD; VANDENBRANDEN M; WRIGHTON SA; JONES DR;
Indirizzi:
WISHARD MEM HOSP,DIV CLIN PHARMACOL,OPW 320,1001 W 10TH ST INDIANAPOLIS IN 46202 PURDUE UNIV,SCH PHARM,DEPT PHARM PRACTICE W LAFAYETTE IN 47907 INDIANA UNIV,SCH MED,DEPT MED INDIANAPOLIS IN 46202 ELI LILLY & CO INDIANAPOLIS IN 46285
Titolo Testata:
Biochemical pharmacology
fascicolo: 9, volume: 47, anno: 1994,
pagine: 1643 - 1653
SICI:
0006-2952(1994)47:9<1643:RBOMBM>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
ERYTHROMYCIN BREATH TEST; HUMAN-LIVER-MICROSOMES; GENETIC-POLYMORPHISM; HEALTHY-SUBJECTS; DRUG-METABOLISM; N-DEMETHYLATION; RABBIT LIVER; HUMAN-FETAL; IDENTIFICATION; OXIDATION;
Keywords:
CYTOCHROME P450; CYP3A SUBFAMILY; MIDAZOLAM; HYDROXYLATION; HUMAN LIVER MICROSOMES; REGIOSELECTIVE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
J.C. Gorski et al., "REGIOSELECTIVE BIOTRANSFORMATION OF MIDAZOLAM BY MEMBERS OF THE HUMANCYTOCHROME-P450-3A (CYP3A) SUBFAMILY", Biochemical pharmacology, 47(9), 1994, pp. 1643-1653

Abstract

The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and high substrate concentration (400 muM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold far 1'- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively. Six fetalhepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were highly correlated (r(2) = 0.99 and 0.97, P < 0.01, respectively). The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 mu M) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r(2) = 0.95 and 0.92, respectively), 6 beta-hydroxylate testosterone (r(2) = 0.96 and 0.96, respectively), and theCYP3A4 content of the samples (r(2) = 0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001). Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b(5), and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolamformation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/07/20 alle ore 20:02:02