title: Effects of CYP3A4/5 and ABCB1 genetic polymorphisms on carbamazepine metabolism and transport in Chinese patients with epilepsy treated with carbamazepine in monotherapy and bitherapy.
abstract: OBJECTIVE
  To examine the effects of cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette sub-family B member 1 (ABCB1) genetic polymorphisms on carbamazepine (CBZ) plasma concentrations in Chinese patients with epilepsy using CBZ as monotherapy and bitherapy with phenytoin (PHT), phenobarbital (PB), or valproic acid (VPA).
  
  
  METHODS
  Eighty-eight Chinese patients with epilepsy were recruited from Xiangya Hospital Central South University, of whom 66 patients were placed in the CBZ monotherapy group, 10 patients were placed in the CBZ bitherapy group combined with one enzyme-inducing anti-seizure medications (PHT or PB), and 12 patients were placed in the CBZ bitherapy group combined with VPA. Carbamazepine and carbamazepine-10,11-epoxide (CBZ-E) plasma concentration of these patients were measured. In addition, the genetic polymorphisms of rs4646440 and rs2242480 in the CYP3A4 gene, rs15524 and rs776746 in the CYP3A5 gene, and rs1045642, rs2032582, rs10234411 and rs1128503 in the ABCB1 gene of the cohort were genotyped. Subsequently, the associations between CBZ plasma concentrations and target single-nucleotide polymorphisms (SNPs), as well as haplotypes, were analysed.
  
  
  RESULTS
  In the CBZ monotherapy group, dose-adjusted CBZ concentrations were not associated with the eight SNPs and haplotypes. In the CBZ+PHT/PB group, rs776746, rs15524 and rs15524-rs776746 GT, AC haplotype were significantly associated with dose-adjusted CBZ plasma concentration (P=0.006, 0.006, 0.003, 0.003, respectively) and CBZ plus CBZ-E concentrations (P=0.006, 0.006, 0.006, 0.006, respectively); rs2032582, rs10234411 and rs2032582-rs10234411 AT, and CA haplotype were associated with the CBZ-E/CBZ ratio (P=0.007, 0.004, 0.004, 0.007, respectively).
  
  
  CONCLUSIONS
  rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB.
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Dan-Qi
authors.initials: DQ
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Yang-Hao
authors.initials: YH
authors.lastname: Sheng
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Can
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China. Electronic address: botingzhou0918@126.com.
authors.forename: Bo-Ting
authors.initials: BT
authors.lastname: Zhou
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002681:China; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010634:Phenobarbital / Q000627:therapeutic use; D010672:Phenytoin / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D014635:Valproic Acid / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; C473667:cytochrome P-450 CYP3A45; D010634:Phenobarbital
keywords: ABCB1; CYP3A4; CYP3A5; Carbamazepine; Genetic polymorphism; Plasma concentration