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Title: CYP3A5 gene variation influences cyclosporine A metabolite formation and renal cyclosporine disposition.

Authors: Zheng, Songmao; Tasnif, Yasar; Hebert, Mary F; Davis, Connie L; Shitara, Yoshihisa; Calamia, Justina C; Lin, Yvonne S; Shen, Danny D; Thummel, Kenneth E

Published In Transplantation, (2013 Mar 27)

Abstract: Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend on the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intrarenal CsA accumulation.An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by liquid chromatography-mass spectometry. In vitro incubations of CsA, AM1, AM9, and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9.The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared with CYP3A5 nonexpressors, the average blood area under the concentration-time curve (AUC) for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P=0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance based on a 48-hr collection was 20.4% lower in CYP3A5 expressors compared with CYP3A5 nonexpressors (4.2±1.0 and 5.3±1.3 mL/min, respectively; P=0.037), which is suggestive of CYP3A5-dependent intrarenal CsA metabolism.At steady state, intrarenal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient variability in the risk of CsA-induced nephrotoxicity.

PubMed ID: 23354298 Exiting the NIEHS site

MeSH Terms: Administration, Oral; Adult; Area Under Curve; Chromatography, Liquid/methods; Cyclosporine/pharmacology*; Cytochrome P-450 CYP3A/genetics*; Female; Genetic Variation*; Genotype; Glomerular Filtration Rate; Humans; Immunosuppressive Agents/pharmacology; Kidney/drug effects*; Male; Mass Spectrometry/methods; Pharmacogenetics/methods; Time Factors

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