Effects of CYP3A5, MDR1 and CACNA1C polymorphisms on the oral disposition and response of nimodipine in a Chinese cohort.
OBJECTIVE
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.
Zhao
Ying
Y
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Zhai
Desheng
D
He
Hui
H
Li
Tingting
T
Chen
Xijing
X
Ji
Hui
H
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000284:Administration, Oral; D000483:Alleles; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002681:China; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D009553:Nimodipine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C079146:CACNA1C protein, human; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017931:DNA Primers; D009553:Nimodipine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A