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Kelly PA, Wang H, Napoli KL, et al. Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur J Drug Metab Pharmacokinet. 1999;24(4):321-8doi: 10.1007/BF03190040.
Kelly, P. A., Wang, H., Napoli, K. L., Kahan, B. D., & Strobel, H. W. (1999). Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. European journal of drug metabolism and pharmacokinetics, 24(4), 321-8. https://doi.org/10.1007/BF03190040
Kelly, P A, et al. "Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4." European journal of drug metabolism and pharmacokinetics vol. 24,4 (1999): 321-8. doi: https://doi.org/10.1007/BF03190040
Kelly PA, Wang H, Napoli KL, Kahan BD, Strobel HW. Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur J Drug Metab Pharmacokinet. 1999 Oct-Dec;24(4):321-8. doi: 10.1007/BF03190040. PMID: 10892895.
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Eur J Drug Metab Pharmacokinet. 1999 Oct-Dec;24(4):321-8. doi: 10.1007/BF03190040.

Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4.

European journal of drug metabolism and pharmacokinetics

P A Kelly, H Wang, K L Napoli, B D Kahan, H W Strobel

Affiliations

  1. Division of Immunology and Organ Transplantation, University of Texas-Houston Health Science Center, and University of Houston, 77030, USA.

PMID: 10892895 DOI: 10.1007/BF03190040

Abstract

The ability of P450 3A9 to transform cyclosporine was studied and compared to 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 AM1 (63% of metabolites formed) while P450 3A9 formed AM4n (59% of metabolites formed). Ketoconazole (0.5 microM) completely inhibited P450 3A9 catalyzed formation of AM1 and AM9 and reduced AM4n formation to 28% of control. AM4n, AM1, and AM9 formation catalyzed by P450 3A4 was reduced to 50%, 30%, and 10% of control, respectively, by 0.5 microM ketoconazole. Troleandomycin (> 10 microM) inhibited the formation of AM4n by P450 3A4 and P450 3A9 to 60-70% of control, while the production 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 microM) 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 to multiple metabolites similar to those generated by human P450 3A4.

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