Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: Consequences for pravastatin pharmacokinetics

Yohei Nishizato, Ichiro Ieiri, Hiroshi Suzuki, Miyuki Kimura, Kiyoshi Kawabata, Takeshi Hirota, Hiroshi Takane, Shin Irie, Hiroyuki Kusuhara, Yoko Urasaki, Akinori Urae, Shun Higuchi, Kenji Otsubo, Yuichi Sugiyama

Research output: Contribution to journalArticlepeer-review

445 Citations (Scopus)

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). Conclusion: 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.

Original languageEnglish
Pages (from-to)554-565
Number of pages12
JournalClinical Pharmacology and Therapeutics
Volume73
Issue number6
DOIs
Publication statusPublished - Jun 1 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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