title: CYP1A2 genotype affects carbamazepine pharmacokinetics in children with epilepsy.
abstract: OBJECTIVE
  The purpose of this study is to investigate the effect of two of the most important functional CYP1A2 variations -3860G > A and -163C > A on carbamazepine pharmacokinetics in Serbian pediatric epileptic patients.
  
  
  METHODS
  The study involved 40 Serbian pediatric epileptic patients on steady-state carbamazepine treatment. Genotyping for -3860G > A and -163C > A was carried out using PCR-RFLP method, and carbamazepine plasma concentrations were determined by high pressure liquid chromatography (HPLC) method. For pharmacokinetic analysis, NONMEM software with implementation of ADVAN 1 subroutine was used.
  
  
  RESULTS
  CYP1A2 polymorphism -163C > A was found at the frequency of 65.0 %, while -3860G > A was not detected. The correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in carriers of -163C/C and C/A genotypes (r = 0.68, p = 0.0004). The equation that described population clearance (CL) was CL (l/h) = 0.176 + 0.0484 * SEX + 0.019 * CYP1A2 + 0.000156 * DD, where SEX has a value of 1 if male and 0 if female, CYP1A2 has a value of 1 if -163A/A and 0 if -163C/C or C/A, and DD is the total carbamazepine daily dose (mg/day).
  
  
  CONCLUSIONS
  CYP1A2 -163A/A genotype influence carbamazepine pharmacokinetics. In addition to sex and total carbamazepine daily dose, -163C > A CYP1A2 polymorphism should be considered as a predictor of carbamazepine clearance.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia. natashadj2002@yahoo.com.
authors.forename: Natasa
authors.initials: N
authors.lastname: Djordjevic
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Dragana Dragas
authors.initials: DD
authors.lastname: Milovanovic
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Marija
authors.initials: M
authors.lastname: Radovanovic
authors.affiliation: Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Radosavljevic
authors.affiliation: Department of Pediatrics, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Obradovic
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Mihajlo
authors.initials: M
authors.lastname: Jakovljevic
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Dragan
authors.initials: D
authors.lastname: Milovanovic
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Jasmina R
authors.initials: JR
authors.lastname: Milovanovic
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34 000, Kragujevac, Serbia.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Jankovic
mesh_terms: D000293:Adolescent; D002220:Carbamazepine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D002220:Carbamazepine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2
keywords: CYP1A2 genotype; Carbamazepine; Children; Pharmacokinetics