title: Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing.
abstract: OBJECTIVE
  To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide).
  
  
  METHODS
  A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS.
  
  
  RESULTS
  The AUC and t1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC0-12 ratio of lansoprazole in EMs and PMs was 1:3.3 - 4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose.
  
  
  CONCLUSIONS
  The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs.
authors.affiliation: Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Masato
authors.initials: M
authors.lastname: Fukae
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Yukie
authors.initials: Y
authors.lastname: Ando
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Shunji
authors.initials: S
authors.lastname: Matsuki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Matsuguma
authors.forename: Eri
authors.initials: E
authors.lastname: Kanda
authors.forename: Mariko
authors.initials: M
authors.lastname: Deguchi
authors.forename: Shin
authors.initials: S
authors.lastname: Irie
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan / Q000494:pharmacology; D005838:Genotype; D005905:Glyburide / Q000493:pharmacokinetics; D006801:Humans; D064747:Lansoprazole; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics*; D014859:Warfarin / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D027361:Organic Anion Transporters; D064747:Lansoprazole; D014859:Warfarin; D003915:Dextromethorphan; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D005905:Glyburide