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Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2003 Jun; Vol. 73 (6), pp. 554-65. - Publication Year :
- 2003
-
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.<br />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.<br />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).<br />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.
- Subjects :
- Adult
Alleles
Area Under Curve
Asian People
Biotransformation
Black People
DNA analysis
DNA biosynthesis
DNA genetics
Gene Frequency
Haplotypes
Humans
Japan
Polymorphism, Genetic genetics
Reverse Transcriptase Polymerase Chain Reaction
Terminology as Topic
White People
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacokinetics
Liver-Specific Organic Anion Transporter 1 genetics
Organic Anion Transporters, Sodium-Independent genetics
Pravastatin pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0009-9236
- Volume :
- 73
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 12811365
- Full Text :
- https://doi.org/10.1016/S0009-9236(03)00060-2