title: Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy.
abstract: OBJECTIVE
  The aim of this study was to evaluate the association of genetic variants in the major genes involved in carbamazepine (CBZ) metabolism and transport with its pharmacokinetics in epilepsy patients.
  
  
  METHODS
  Twenty-five SNPs within seven CBZ pathway genes, namely CYP3A4, CYP3A5, EPHX1, NR1I2, UGT2B7, ABCB1 and ABCC2, were analyzed for association with CBZ pharmacokinetics in 90 epilepsy patients.
  
  
  RESULTS
  The CYP3A4*1B SNP was significantly associated with CBZ clearance. Significant association of EPHX1 SNPs was observed with greater carbamazepine-10,11-trans dihydrodiol:carbamazepine 10-11 epoxide ratios. Among drug transporters, ABCB1 and ABCC2 SNPs were significantly associated with altered CBZ clearance.
  
  
  CONCLUSIONS
  SNPs within CBZ pathway genes contribute to interpatient variation in CBZ pharmacokinetics and might contribute to pharmacoresistant epilepsy. Although our results need further clinical validation in a larger patient cohort, they indicate that genetic variation in CBZ pathway genes could influence its pharmacokinetics, and hence would have clinical significance.
authors.affiliation: Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Yogita Ghodke
authors.initials: YG
authors.lastname: Puranik
authors.forename: Angela K
authors.initials: AK
authors.lastname: Birnbaum
authors.forename: Susan E
authors.initials: SE
authors.lastname: Marino
authors.forename: Ghada
authors.initials: G
authors.lastname: Ahmed
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
authors.forename: Rory P
authors.initials: RP
authors.lastname: Remmel
authors.forename: Ilo E
authors.initials: IE
authors.lastname: Leppik
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000235:genetics; D002220:Carbamazepine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; D004851:Epoxide Hydrolases; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C000625852:NR1I2 protein, human; C510163:CYP3A4 protein, human; C522330:EPHX1 protein, human