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CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation.
Clin Pharmacol Ther. 2004 May; 75(5):422-33.CP

Abstract

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.

Authors+Show Affiliations

Unité INSERM UMR S490, Centre Universitaire des Saints-Péres, Paris, France. Dany.Anglicheau@univ-paris5.frNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15116055

Citation

Anglicheau, Dany, et al. "CYP3A5 and MDR1 Genetic Polymorphisms and Cyclosporine Pharmacokinetics After Renal Transplantation." Clinical Pharmacology and Therapeutics, vol. 75, no. 5, 2004, pp. 422-33.
Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther. 2004;75(5):422-33.
Anglicheau, D., Thervet, E., Etienne, I., Hurault De Ligny, B., Le Meur, Y., Touchard, G., Büchler, M., Laurent-Puig, P., Tregouet, D., Beaune, P., Daly, A., Legendre, C., & Marquet, P. (2004). CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clinical Pharmacology and Therapeutics, 75(5), 422-33.
Anglicheau D, et al. CYP3A5 and MDR1 Genetic Polymorphisms and Cyclosporine Pharmacokinetics After Renal Transplantation. Clin Pharmacol Ther. 2004;75(5):422-33. PubMed PMID: 15116055.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. AU - Anglicheau,Dany, AU - Thervet,Eric, AU - Etienne,Isabelle, AU - Hurault De Ligny,Bruno, AU - Le Meur,Yannick, AU - Touchard,Guy, AU - Büchler,Matthias, AU - Laurent-Puig,Pierre, AU - Tregouet,David, AU - Beaune,Philippe, AU - Daly,Ann, AU - Legendre,Christophe, AU - Marquet,Pierre, PY - 2004/4/30/pubmed PY - 2004/5/28/medline PY - 2004/4/30/entrez SP - 422 EP - 33 JF - Clinical pharmacology and therapeutics JO - Clin Pharmacol Ther VL - 75 IS - 5 N2 - 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. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/15116055/CYP3A5_and_MDR1_genetic_polymorphisms_and_cyclosporine_pharmacokinetics_after_renal_transplantation_ L2 - https://doi.org/10.1016/j.clpt.2004.01.009 DB - PRIME DP - Unbound Medicine ER -