title: Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics.
abstract: OBJECTIVE
  Our objective was to quantitate the contribution of the genetic polymorphisms of the genes for 2 human organic anion transporters-organic anion transporting polypeptide C (OATP-C) and organic anion transporter 3 (OAT3)-to the pharmacokinetics of pravastatin.
  
  
  METHODS
  Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformation polymorphism analysis, after sequencing with deoxyribonucleic acid obtained from 120 healthy volunteers. To examine whether polymorphisms in these 2 genes of interest alter transport activity, we conducted a clinical study (n = 23) with pravastatin as a selective probe drug.
  
  
  RESULTS
  Among 120 healthy individuals, 5 nonsynonymous variants and 1 nonsynonymous variant were observed in the OATP-C and OAT3 genes, respectively. The polymorphisms in the OAT3 gene did not appear to be associated with changes in renal and tubular secretory clearance. In contrast, the OATP-C variants were associated with differences in the disposition kinetics of pravastatin. Subjects with the OATP-C*15 allele (Asp130Ala174) had a reduced total and nonrenal clearance, as compared with those with the OATP-C*1b allele (Asp130Val174); nonrenal clearance values in *1b/*1b (n = 4), *1b/*15 (n = 9), and *15/*15 (n = 1) subjects were 2.01 +/- 0.42 L. kg(-1). h(-1), 1.11 +/- 0.34 L. kg(-1). h(-1), and 0.29 L. kg(-1). h(-1), respectively, and the difference between *1b/*1b and *1b/*15 subjects was significant (P <.05).
  
  
  CONCLUSIONS
  Certain commonly occurring single-nucleotide polymorphisms in OATP-C, such as T521C (Val174Ala), are likely to be associated with altered pharmacokinetics of pravastatin. Large clinical studies are needed to confirm these observations.
authors.affiliation: Division of Pharmaceutical Sciences, Department of Clinical Pharmacokinetics, Graduate School, Kyushu University, Fukuoka, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Nishizato
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kawabata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takane
authors.forename: Shin
authors.initials: S
authors.lastname: Irie
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Urasaki
authors.forename: Akinori
authors.initials: A
authors.lastname: Urae
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Otsubo
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People; D001711:Biotransformation; D044383:Black People; D004247:DNA / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007564:Japan; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D017035:Pravastatin / Q000493:pharmacokinetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009626:Terminology as Topic; D044465:White People
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D004247:DNA; D017035:Pravastatin