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Titolo:
Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4
Autore:
Kelly, PA; Wang, H; Napoli, KL; Kahan, BD; Strobel, HW;
Indirizzi:
Univ Texas, Hlth Sci Ctr, Sch Med, Div Immunol & Organ Transplantat, Houston, TX 77030 USA Univ Texas Houston TX USA 77030 Organ Transplantat, Houston, TX 77030 USA Univ Texas, Hlth Sci Ctr, Dept Biochem & Mol Biol, Houston, TX 77030 USA Univ Texas Houston TX USA 77030 Biochem & Mol Biol, Houston, TX 77030 USA Univ Houston, Coll Pharm, Houston, TX 77030 USA Univ Houston Houston TX USA 77030 ston, Coll Pharm, Houston, TX 77030 USA
Titolo Testata:
EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS
fascicolo: 4, volume: 24, anno: 1999,
pagine: 321 - 328
SICI:
0378-7966(199910/12)24:4<321:MOCBCP>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER CYTOCHROME-P-450; PITUITARY-GONADAL AXIS; RAT-LIVER; DEPENDENT EXPRESSION; DRUG-INTERACTIONS; GROWTH-HORMONE; GENE FAMILY; A OXIDASE; TESTOSTERONE; PURIFICATION;
Keywords:
cytochrome P450; drug metabolism; cyclosporine; cytochrome P450 3A4; cytochrome P450 3A9;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Kahan, BD Univ Texas, Hlth Sci Ctr, Sch Med, Div Immunol & Organ Transplantat, 6431 Fannin St,Suite 6-240, Houston, TX 77030 USA Univ Texas 6431 Fannin St,Suite 6-240 Houston TX USA 77030 0 USA
Citazione:
P.A. Kelly et al., "Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4", EUR J DRUG, 24(4), 1999, pp. 321-328

Abstract

The ability of P450 3A9 to transform cyclosporine was studied and comparedto that of human P450 3A4. Purified P450 3A4 and P450 3A9 proteins were reconstituted in a system containing potassium phosphate buffer, lipids, NADPH-P450 reductase, and glutathione with NADPH added to initiate the reaction. Cyclosporine was added alone and with or without the inhibitors, ketoconazole or troleandomycin. High performance liquid chromatography with ultraviolet (HPLC/UV) techniques were used to analyze for cyclosporine metabolites. Both P450 3A4 and P450 3A9 transformed cyclosporine to three metabolites:AM1, AM9, and AM4n. P450 3A4 predominantly formed AMI (63% of metabolites formed) while P450 3A9 formed AM4n (59% of metabolites formed). Ketoconazole (0.5 mu M) completely inhibited P450 3A9 catalyzed formation of AM1 and AM9 and reduced AM4n formation to 28% of control. AM4n, AMI, and AM9 formation catalyzed by P450 3A4 was reduced to 50%, 30%, and 10% of control, respectively, by 0.5 mu M ketoconazole. Troleandomycin (> 10 mu M) inhibited theformation of AM4n by P450 3A4 and P450 3A9 to 60-70% of control, while theproduction of AM1 by P450 3A4 was increased to 120% of control and the production of AM1 by P450 3A9 was inhibited to 50% of control. Inhibition of P450 3A4 by troleandomycin (> 10 mu M) reduced the formation of AM9 to 40% of control, but only reduced P450 3A9 formation of AM9 to 80% of control. This study shows that rat P450 3A9 is capable of transforming cyclosporine tomultiple metabolites similar to those generated by human P450 3A4.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 09:55:26