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CYP3A5 and MDR1 Genetic Polymorphisms and Cyclosporine Pharmacokinetics After Renal Transplantation
Author(s) -
Anglicheau Dany,
Thervet Eric,
Etienne Isabelle,
Hurault De Ligny Bruno,
Le Meur Yannick,
Touchard Guy,
Büchler Matthias,
LaurentPuig Pierre,
Tregouet David,
Beaune Philippe,
Daly Ann,
Legendre Christophe,
Marquet Pierre
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.01.009
Subject(s) - single nucleotide polymorphism , pharmacokinetics , cyp3a5 , ciclosporin , linkage disequilibrium , pharmacology , haplotype , genotype , medicine , transplantation , biology , genetics , gene
Background The immunosuppressive drug cyclosporine (INN, ciclosporin), whose pharmacokinetic characteristics vary greatly among individuals, is a substrate for cytochrome P450 (CYP) 3A and P‐glycoprotein, the product of the multidrug resistance 1 ( MDR1 ) gene. Some of the single nucleotide polymorphisms (SNPs) in these genes are associated with deficient protein expression and reduced in vivo activity. We postulated that, in renal transplant recipients, these SNPs could be associated with interindividual variations in cyclosporine pharmacokinetics. Purpose In 106 renal transplant patients, we evaluated retrospectively the effects of 4 MDR1 SNPs [T−129C, C1236T, G2677(T,A), and C3435T] and of the CYP3A5*1/*3 SNP on cyclosporine pharmacokinetic parameters and exposure indices. Results The CYP3A5*1 allele was present in 8.5% of patients. The MDR1 C1236T, G2677(T,A), and C3435T SNPs were frequent (17.9%, 18.9%, and 33%, respectively, for the variant homozygous genotype) and exhibited incomplete linkage disequilibrium. None of the cyclosporine pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism. Patients with the wild‐type genotype in MDR1 C1236T SNP had slightly but significantly lower dose‐adjusted peak drug concentrations (−16%) ( P < .02) and dose‐adjusted area under the concentration‐time curve (AUC) values over the first 4 hours (−14%) ( P < .05) as compared with mutated allele carriers. Haplotype analysis including MDR1 C1236T, G2677(T,A), and C3435T SNPs showed no significant association between haplotypes and cyclosporine pharmacokinetics or systemic exposure, although there was a nonsignificant trend toward higher dose‐adjusted AUC values over the first 4 hours and AUC over the 12‐hour administration interval for the T‐T‐T haplotype. Conclusion The presence of the CYP3A5 SNP does not explain the high variability of cyclosporine pharmacokinetics in stable renal transplant patients. Despite the weak association found for the MDR1 C1236T SNP, MDR1 SNPs are unlikely to be useful for cyclosporine dose optimization in clinical practice. Clinical Pharmacology & Therapeutics (2004) 75 , 422–433; doi: 10.1016/j.clpt.2004.01.009