title: Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients.
abstract: OBJECTIVE
  The calcium channel blocker diltiazem has been used widely as a cyclosporine (CsA)/tacrolimus-sparing agent. However, considerable interpatient variability in diltiazem's CsA/tacrolimus-sparing effect has been observed in many clinical studies. This study was carried out to investigate the impacts of the CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.
  
  
  METHODS
  Two hundred and twenty-five Chinese renal transplant patients were genotyped for CYP3A4*1G and CYP3A5*3. The predose and post-dose plasma concentrations of diltiazem and its main metabolisms were determined by HPLC. The relationships between the genotypes and pharmacokinetics were investigated.
  
  
  CONCLUSIONS
  The dose-adjusted concentrations and pharmacokinetics of diltiazem and its main metabolites were significantly affected by CYP3A4 *1G and CYP3A5*3 alleles. Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted trough concentration and AUC of diltiazem and its main metabolites compared with those with CYP3A4*1G*1G(P<0·05). The dose-adjusted trough levels and AUC of diltiazem and its main metabolites were significantly lower in CYP3A5*1*1 carriers than in CYP3A5*3 carriers (P < 0·05).
  
  
  CONCLUSIONS
  The CYP3A4*1G and CYP3A5*3 genetic polymorphisms are closely related to the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: X-C
authors.initials: XC
authors.lastname: Zuo
authors.affiliation: Department of Transplantation, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: K
authors.initials: K
authors.lastname: Chen
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: J-L
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Q-J
authors.initials: QJ
authors.lastname: Chen
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Y-N
authors.initials: YN
authors.lastname: Zhou
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: H
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Transplantation, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Transplantation, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Clinical Pharmacy and Pharmacology Research Institute, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Y-X
authors.initials: YX
authors.lastname: Peng
authors.affiliation: Department of Transplantation, Third Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Ming
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002681:China; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004110:Diltiazem / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D002121:Calcium Channel Blockers; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem
keywords: calcium channel blocker; clinical pharmacokinetics; cytochrome P450; diltiazem; genetic polymorphisms