Document Detail


CYP3A5 gene variation influences cyclosporine A metabolite formation and renal cyclosporine disposition.
MedLine Citation:
PMID:  23354298     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Authors:
Songmao Zheng; Yasar Tasnif; Mary F Hebert; Connie L Davis; Yoshihisa Shitara; Justina C Calamia; Yvonne S Lin; Danny D Shen; Kenneth E Thummel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Transplantation     Volume:  95     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-19     Completed Date:  2013-05-13     Revised Date:  2014-05-30    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  821-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
P30 ES007033/ES/NIEHS NIH HHS; P30 ES07033/ES/NIEHS NIH HHS; R01 GM068871/GM/NIGMS NIH HHS; R01 GM068871/GM/NIGMS NIH HHS; U01 GM092676/GM/NIGMS NIH HHS; U01 GM092676/GM/NIGMS NIH HHS; UL1 98195-7610//PHS HHS; UL1 TR000423/TR/NCATS NIH HHS
Chemical
Reg. No./Substance:
0/AM 19; 0/Immunosuppressive Agents; 83HN0GTJ6D/Cyclosporine; EC 1.14.14.1/CYP3A5 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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