Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics.
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.
Nishizato
Yohei
Y
Division of Pharmaceutical Sciences, Department of Clinical Pharmacokinetics, Graduate School, Kyushu University, Fukuoka, Japan.
Ieiri
Ichiro
I
Suzuki
Hiroshi
H
Kimura
Miyuki
M
Kawabata
Kiyoshi
K
Hirota
Takeshi
T
Takane
Hiroshi
H
Irie
Shin
S
Kusuhara
Hiroyuki
H
Urasaki
Yoko
Y
Urae
Akinori
A
Higuchi
Shun
S
Otsubo
Kenji
K
Sugiyama
Yuichi
Y
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
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