Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2003-09

AUTHORS

Dennis A. Hesselink, Ron H. N. Schaik, Ilse P. Heiden, Marloes Werf, Peter J. H. Smak Gregoor, Jan Lindemans, Willem Weimar, Teun Gelder

ABSTRACT

BACKGROUND: The calcineurin inhibitors cyclosporine (INN, cyclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-1. OBJECTIVE: Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics. METHODS: Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype. RESULTS: Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P <.0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P =.003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations. CONCLUSION: As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4*1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes. More... »

PAGES

245-254

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1016/s0009-9236(03)00168-1

    DOI

    http://dx.doi.org/10.1016/s0009-9236(03)00168-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1026086420

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/12966368


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