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In vitro metabolism of cyclosporine A by human kidney CYP3A5.

Publication ,  Journal Article
Dai, Y; Iwanaga, K; Lin, YS; Hebert, MF; Davis, CL; Huang, W; Kharasch, ED; Thummel, KE
Published in: Biochem Pharmacol
November 1, 2004

The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20 microM CsA) was positively associated with the detection of CYP3A5 protein and presence of the CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active CYP3A5*1-positive renal microsomal preparation yielded an apparent Km (15.5 microM) similar to that of CYP3A5 (11.3 microM). Ketoconazole (200 nM) inhibited renal AM9 formation by 22-55% over a CsA concentration range of 2-45 microM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in CYP3A5*1/*3 livers, compared to CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a CYP3A5*1/*3 genotype, compared to those with a CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type CYP3A5*1 allele.

Duke Scholars

Published In

Biochem Pharmacol

DOI

ISSN

0006-2952

Publication Date

November 1, 2004

Volume

68

Issue

9

Start / End Page

1889 / 1902

Location

England

Related Subject Headings

  • Testosterone
  • Pharmacology & Pharmacy
  • Microsomes
  • Kinetics
  • Kidney
  • Humans
  • Genotype
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • Cyclosporine
 

Citation

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Dai, Y., Iwanaga, K., Lin, Y. S., Hebert, M. F., Davis, C. L., Huang, W., … Thummel, K. E. (2004). In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol, 68(9), 1889–1902. https://doi.org/10.1016/j.bcp.2004.07.012
Dai, Yang, Kazunori Iwanaga, Yvonne S. Lin, Mary F. Hebert, Connie L. Davis, Weili Huang, Evan D. Kharasch, and Kenneth E. Thummel. “In vitro metabolism of cyclosporine A by human kidney CYP3A5.Biochem Pharmacol 68, no. 9 (November 1, 2004): 1889–1902. https://doi.org/10.1016/j.bcp.2004.07.012.
Dai Y, Iwanaga K, Lin YS, Hebert MF, Davis CL, Huang W, et al. In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol. 2004 Nov 1;68(9):1889–902.
Dai, Yang, et al. “In vitro metabolism of cyclosporine A by human kidney CYP3A5.Biochem Pharmacol, vol. 68, no. 9, Nov. 2004, pp. 1889–902. Pubmed, doi:10.1016/j.bcp.2004.07.012.
Dai Y, Iwanaga K, Lin YS, Hebert MF, Davis CL, Huang W, Kharasch ED, Thummel KE. In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol. 2004 Nov 1;68(9):1889–1902.
Journal cover image

Published In

Biochem Pharmacol

DOI

ISSN

0006-2952

Publication Date

November 1, 2004

Volume

68

Issue

9

Start / End Page

1889 / 1902

Location

England

Related Subject Headings

  • Testosterone
  • Pharmacology & Pharmacy
  • Microsomes
  • Kinetics
  • Kidney
  • Humans
  • Genotype
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP3A
  • Cyclosporine