title: Pregnane X receptor and hepatocyte nuclear factor 4α polymorphisms are cooperatively associated with carbamazepine autoinduction.
abstract: OBJECTIVE
  We attempted to clarify the influence of polymorphisms of nuclear receptors on carbamazepine therapy.
  
  
  METHODS
  The common polymorphisms of nuclear receptors--a tentative pregnane X receptor (PXR)*1B, hepatocyte nuclear factor 4α (HNF4α) rs2071197 (c.115+308G>A), and cytochrome P450 3A5*3 polymorphisms--were genotyped in 168 Japanese patients with epilepsy. The associations of these polymorphisms with the disposition, clinical efficacy, and incidence of adverse effects of carbamazepine treatment were retrospectively investigated in 104 patients treated with carbamazepine alone. The associations with disposition were also assessed in 64 patients treated with carbamazepine and other antiepileptic drugs, which constituted the internal replication group, and in the combined 168 patients.
  
  
  RESULTS
  Neither polymorphism alone affected the carbamazepine disposition, but a significant interactive effect of PXR*1B and HNF4α rs2071197 polymorphisms on the concentration-to-dose (C/D) ratios was observed (P=0.027). The C/D ratios among patients with the HNF4α G/G genotype were higher in PXR*1B carriers than in PXR*1B noncarriers, which was confirmed in the internal replication and combined groups. In patients with the HNF4α G/G genotype, the rate of freedom from seizures until 3 months after starting carbamazepine therapy was significantly greater and the time required to reach the dose required for seizure freedom was shorter in PXR*1B carriers than in PXR*1B noncarriers.
  
  
  CONCLUSIONS
  These results suggest that PXR*1B, in combination with HNF4α rs2071197, might be associated with the C/D ratios and the duration to reach the maintenance dose of carbamazepine therapy, thus indicating an influence upon the autoinduction of the carbamazepine metabolism.
authors.affiliation: aDivision of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences bCenter for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto cDepartment of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki dKumamoto Saishunso National Hospital, Koshi, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Saruwatari
authors.forename: Shiho
authors.initials: S
authors.lastname: Yoshida
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okada
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogusu
authors.forename: Kousuke
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kentaro
authors.initials: K
authors.lastname: Oniki
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.forename: Takateru
authors.initials: T
authors.lastname: Ishitsu
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002220:Carbamazepine / Q000627:therapeutic use*; D002648:Child; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D002220:Carbamazepine; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A