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Effects of CYP3A5, MDR1 and CACNA1C polymorphisms on the oral disposition and response of nimodipine in a Chinese cohort

  • Pharmacogenetics
  • Published:
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Abstract

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 lnCmax or \(\ln {\text{AUC}}_{0 - \infty } \) 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.

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Abbreviations

CACNA1C :

the calcium channel, voltage-dependent, L-type alpha 1C subunit

CYP3A5 :

cytochrome P450 3A5 gene

DBP:

diastolic blood pressure

SBP:

systolic blood pressure

SNP:

single nucleotide polymorphism

References

  1. Langley M, Sorkin E (1989) Nimodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cerebrovascular disease. Drugs 37:669–699

    Article  PubMed  CAS  Google Scholar 

  2. Keyrouz SG, Diringer MN (2007) Clinical review: prevention and therapy of vasospasm in subarachnoid hemorrhage. Crit Care 11(4):220

    Article  PubMed  Google Scholar 

  3. Sobrado M, López MG, Carceller F, García AG, Roda JM (2003) Combined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase bcl-2 expression after focal cerebral ischemia. Neuroscience 118(1):107–113

    Article  PubMed  CAS  Google Scholar 

  4. López-Arrieta JM, Birks J (2002) Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev (3):CD000147

  5. Liu XQ, Ren YL, Qian ZY, Wang GJ (2000) Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes. Acta Pharmacol Sin 21(8):690–694

    PubMed  CAS  Google Scholar 

  6. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J et al (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27(4):383–391

    Article  PubMed  CAS  Google Scholar 

  7. Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T et al (2002) Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 71(4):297–303

    Article  PubMed  CAS  Google Scholar 

  8. Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K (2002) Interaction of digoxin with antihypertensive drugs via MDR1. Life Sci 70(13):1491–500

    Google Scholar 

  9. Zhang L, Liu XD, Xie L, Wang GJ (2003) P-glycoprotein restricted transport of nimodipine across blood-brain barrier. Acta Pharmacol Sin 24(9):903–906

    PubMed  CAS  Google Scholar 

  10. Höcht C, Lazarowski A, Gonzalez NN, Auzmendi J, Opezzo JA, Bramuglia GF et al (2007) Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model. Neurosci Lett 413(2):168–172

    Article  PubMed  Google Scholar 

  11. Arnett DK, Claas SA, Glasser SP (2006) Pharmacogenetics of antihypertensive treatment. Vascul Pharmacol 44(2):107–118

    Article  PubMed  CAS  Google Scholar 

  12. Bremer T, Man A, Kask K, Diamond C (2006) CACNA1C polymorphisms are associated with the efficacy of calcium channel blockers in the treatment of hypertension. Pharmacogenomics 7(3):271–279

    Article  PubMed  CAS  Google Scholar 

  13. Song P, Li S, Meibohm B, Gaber AO, Honaker MR, Kotb M et al (2002) Detection of MDR1 single nucleotide polymorphisms C3435T and G2677T using real-time polymerase chain reaction: MDR1 single nucleotide polymorphism genotyping assay. AAPS PharmSci 4(4):E29

    Article  PubMed  Google Scholar 

  14. Yates CR, Zhang W, Song P, Li S, Gaber AO, Kotb M et al (2003) The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. J Clin Pharmacol 43(6):555–564

    PubMed  CAS  Google Scholar 

  15. Zhao Y, Chen X, Yu Q, He H, Sun Y, Gao Z et al (2009) Determination of nimodipine in human plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry and its application to a bioequivalence study. J Chromatogr Sci (In press)

  16. Suh JW, Koo BK, Zhang SY, Park KW, Cho JY, Jang IJ et al (2006) Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. Can Med Assoc J 174(12):1715–1722

    Article  Google Scholar 

  17. Fukuda T, Onishi S, Fukuen S, Ikenaga Y, Ohno M, Hoshino K et al (2004) CYP3A5 genotype did not impact on nifedipine disposition in healthy volunteers. Pharmacogenomics J 4(1):34–39

    Article  PubMed  CAS  Google Scholar 

  18. Kharasch ED, Walker A, Isoherranen N, Hoffer C, Sheffels P, Thummel K et al (2007) Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam. Clin Pharmacol Ther 82(4):410–426

    Article  PubMed  CAS  Google Scholar 

  19. Jin Y, Wang YH, Miao J, Li L, Kovacs RJ, Marunde R et al (2007) Cytochrome P450 3A5 genotype is associated with verapamil response in healthy subjects. Clin Pharmacol Ther 82(5):579–585

    Article  PubMed  CAS  Google Scholar 

  20. Kim KA, Park PW, Lee OJ, Choi SH, Min BH, Shin KH et al (2006) Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects. Clin Pharmacol Ther 80(6):646–656

    Article  PubMed  CAS  Google Scholar 

  21. Deshaies EM, Boulos AS, Drazin D, Popp AJ (2008) Evidence-based pharmacotherapy for cerebral vasospasm. Neurol Res. (Epub)

  22. Tomassoni D, Lanari A, Silvestrelli G, Traini E, Amenta F (2008) Nimodipine and its use in cerebrovascular disease: evidence from recent preclinical and controlled clinical studies. Clin Exp Hypertens 30(8):744–766

    Article  PubMed  CAS  Google Scholar 

  23. Tartara A, Galimberti CA, Manni R, Parietti L, Zucca C, Baasch H et al (1991) Differential effects of valproic acid and enzyme-inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients. Br J Clin Pharmacol 32(3):335–40

    PubMed  CAS  Google Scholar 

  24. Liu XD, Zhang L, Xie L (2003) Effect of P-glycoprotein inhibitors erythromycin and cyclosporin A on brain pharmacokinetics of nimodipine in rats. Eur J Drug Metab Pharmacokinet 28(4):309–313

    PubMed  CAS  Google Scholar 

  25. Kim KA, Park PW, Park JY (2007) Effect of ABCB1 (MDR1) haplotypes derived from G2677T/C3435T on the pharmacokinetics of amlodipine in healthy subjects. Br J Clin Pharmacol 63(1):53–58

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The research was founded by National Natural Science Foundation of China (No. 20 30472060)

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Authors and Affiliations

  1. School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Ying Zhao, Hui He, Tingting Li, Xijing Chen & Hui Ji

  2. School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China

    Ying Zhao

  3. School of Public Health, Centrol South University, Changsha, 410078, China

    Desheng Zhai

  4. Department of Public Health, Xinxiang Medical University, Xinxiang, 453003, China

    Desheng Zhai

Authors
  1. Ying Zhao
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  2. Desheng Zhai
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  3. Hui He
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  4. Tingting Li
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  5. Xijing Chen
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  6. Hui Ji
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Correspondence to Xijing Chen or Hui Ji.

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Zhao, Y., Zhai, D., He, H. et al. Effects of CYP3A5, MDR1 and CACNA1C polymorphisms on the oral disposition and response of nimodipine in a Chinese cohort. Eur J Clin Pharmacol 65, 579–584 (2009). https://doi.org/10.1007/s00228-009-0619-6

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  • DOI: https://doi.org/10.1007/s00228-009-0619-6

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