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MDR1 Haplotypes Do Not Affect the Steady-State Pharmacokinetics of Cyclosporine in Renal Transplant Patients

From the Institute of Clinical Pharmacology (Dr. Mai, Dr. Störmer, Mr. Goldammer, Dr. Johne, Dr. Krüger, Dr. Roots) and the Department of Internal Medicine and Nephrology (Dr. Budde), University Medical Center Charité, Humboldt University of Berlin, Berlin, Germany.

This retrospective study investigated the impact of MDR1 haplotypes derived from the single-nucleotide polymorphisms (SNPs) 2677G>T (exon 21) and 3435C>T (exon 26) on the pharmacokinetics of cyclosporine in 98 renal transplant patients. Based on SNPs 2677 and 3435, four different haplotypes and nine different genotypes were identified in the study sample. Frequencies of SNPs, genotypes, and haplotypes were in agreement with previously reported values. Cyclosporine pharmacokinetics were characterized using a 2-hour AUC (AUC_0-12), trough concentrations (C₀), and blood concentrations 2 hours after cyclosporine administration (C₂). No significant differences in dose-corrected AUC_0-12, C₀, or C₂ values were observed between carriers of different SNP variants and genotypes (Kruskal-Wallis test), as well as between carriers and noncarriers of each haplotype (Mann-Whitney U test). Carriers of haplotype 12 (2677G and 3435T), which has previously been associated with increased digoxin AUC values, had a median AUC_0-12 of 18.9 µg•h•L^-1 (range: 9.0-35.2) compared to 17.5 µg•h•L^-1 (range: 7.5-37.1) in the noncarrier group. It was concluded that MDR1 haplotypes derived from the SNPs 2677G>T (exon 21) and 3435C>T (exon 26) are not associated with cyclosporine pharmacokinetics in renal transplant patients.

Key Words: P-glycoprotein • MDR1 • haplotype • cyclosporine • pharmacokinetics • patients

Address for reprints: Dr. Ingrid Mai, Institut für Klinische Pharmakologie der Charité, Humboldt-Universität zu Berlin, Schumannstr. 20/21, 10098 Berlin, Germany.

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