PURPOSE: Our objective was to study the effects of polymorphic the CYP3A5 (allele *1 and *3), MDR1 [single nucleotide polymorphisms (SNPs) G2677T, C3435T] and CACNA1C (SNPs rs2239128, rs2239050, rs2238032) genes on nimodipine oral disposition and response in healthy Chinese subjects. METHODS: Pharmacokinetics and pharmacodynamics data were obtained from a bioequivalence study, and the same 20 subjects were genotyped for CYP3A, MDR1 and CACNA1C. An additional 41 healthy Chinese subjects were recruited to obtain an indication of the distribution of CACNA1C polymorphisms in the Chinese population. Racial differences in the frequency of CACNA1C alleles were assessed. The phenotype differences between genotypes were analyzed. RESULTS: The allelic frequencies of rs2239050 and rs2238032 in our Chinese cohort were different from those in a Caucasian population (p < 0.01). Subjects with mutant alleles (*3/*3) of the CYP3A5 gene had a decreased oral clearance of nimodipine, with a higher lnC(max) or 1n AUC(0-infinity) compared with those subjects with the heterozygote (*1/*3) or wild type (*1/*1) gene. The CACNA1C rs2239128 C and rs2239050 G SNPs were associated with a stronger efficacy compared with their respective alleles, rs2239128 T and rs2239050 C. MDR1 polymorphisms showed no significance in terms of nimodipine disposition. CONCLUSIONS: The polymorphic CYP3A5 (allele *1 and *3) and CACNA1C genes have effects on nimodipine oral disposition and response in healthy Chinese subjects. The homozygous variant of CYP3A5 (*3/*3) was associated with significantly increased nimodipine exposure. CACNA1C SNPs rs2239128 C and rs2239050 G were associated with a stronger efficacy.
PURPOSE: Our objective was to study the effects of polymorphic the CYP3A5 (allele *1 and *3), MDR1 [single nucleotide polymorphisms (SNPs) G2677T, C3435T] and CACNA1C (SNPs rs2239128, rs2239050, rs2238032) genes on nimodipine oral disposition and response in healthy Chinese subjects. METHODS: Pharmacokinetics and pharmacodynamics data were obtained from a bioequivalence study, and the same 20 subjects were genotyped for CYP3A, MDR1 and CACNA1C. An additional 41 healthy Chinese subjects were recruited to obtain an indication of the distribution of CACNA1C polymorphisms in the Chinese population. Racial differences in the frequency of CACNA1C alleles were assessed. The phenotype differences between genotypes were analyzed. RESULTS: The allelic frequencies of rs2239050 and rs2238032 in our Chinese cohort were different from those in a Caucasian population (p < 0.01). Subjects with mutant alleles (*3/*3) of the CYP3A5 gene had a decreased oral clearance of nimodipine, with a higher lnC(max) or 1n AUC(0-infinity) compared with those subjects with the heterozygote (*1/*3) or wild type (*1/*1) gene. The CACNA1Crs2239128 C and rs2239050 G SNPs were associated with a stronger efficacy compared with their respective alleles, rs2239128 T and rs2239050 C. MDR1 polymorphisms showed no significance in terms of nimodipine disposition. CONCLUSIONS: The polymorphic CYP3A5 (allele *1 and *3) and CACNA1C genes have effects on nimodipine oral disposition and response in healthy Chinese subjects. The homozygous variant of CYP3A5 (*3/*3) was associated with significantly increased nimodipine exposure. CACNA1C SNPs rs2239128 C and rs2239050 G were associated with a stronger efficacy.
Authors: Christian Höcht; Alberto Lazarowski; Nélida N Gonzalez; Jerónimo Auzmendi; Javier A W Opezzo; Guillermo F Bramuglia; Carlos A Taira; Elena Girardi Journal: Neurosci Lett Date: 2007-01-08 Impact factor: 3.046
Authors: E D Kharasch; A Walker; N Isoherranen; C Hoffer; P Sheffels; K Thummel; D Whittington; D Ensign Journal: Clin Pharmacol Ther Date: 2007-06-06 Impact factor: 6.875
Authors: Jason T Davis; Fangwen Rao; Dalal Naqshbandi; Maple M Fung; Kuixing Zhang; Andrew J Schork; Caroline M Nievergelt; Michael G Ziegler; Daniel T O'Connor Journal: J Am Coll Cardiol Date: 2012-06-12 Impact factor: 24.094