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

TLDR

The study aimed to quantify how polymorphisms in the OATP‑C and OAT3 transporter genes affect pravastatin pharmacokinetics and to highlight the need for larger clinical confirmation. Researchers screened 120 healthy volunteers for OATP‑C and OAT3 variants using PCR‑SSCP and sequencing, then evaluated transport activity in a 23‑subject clinical trial with pravastatin as a probe drug. OATP‑C variants, particularly the T521C (Val174Ala) allele, were linked to markedly reduced total and nonrenal clearance of pravastatin, whereas OAT3 polymorphisms showed no effect on renal clearance. Published in Clinical Pharmacology & Therapeutics, 2003, doi:10.1016/S0009-9236(03)00060-2.

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. Clinical Pharmacology & Therapeutics (2003) 73, 554–565; doi: 10.1016/S0009-9236(03)00060-2