Document Detail


Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics.
MedLine Citation:
PMID:  15116054     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: We compared the pharmacogenetic effects of OATP-C (organic anion transporting polypeptide C) *1a, *1b (A388G), and *5 (T521C) haplotypes on single-dose pharmacokinetics of pravastatin in white subjects. METHODS: Thirty healthy white male subjects were grouped according to their OATP-C haplotype. Each group contained 10 individuals who were either homozygous or heterozygous carriers of the *1a, *1b, or *5 haplotype. After a single oral dose of 40 mg pravastatin, we analyzed kinetic parameters of pravastatin disposition. RESULTS: Values for the area under the plasma concentration-time curve from time 0 to 6 hours [AUC(0-6)] in *1a/*1a, *1a/*1b or *1b/*1b, and *1a/*5 individuals were 114.5 +/- 68.6 microg. L(-1). h, 74.8 +/- 35.6 microg. L(-1). h, and 163.0 +/- 64.6 microg. L(-1). h, respectively, with highly significant differences across all 3 study groups (P =.006) and between subjects carrying the *1b and *5 haplotype (P =.002). Strikingly, values of AUC(0-6) from the OATP-C *1b group were more than 60% lower than those derived from carriers of the wild-type OATP-C *1a haplotype, although this difference failed to reach statistical significance. However, the amount of pravastatin excreted into the urine from time 0 to 12 hours [Ae(0-12)] was significantly diminished in the OATP-C *1b haplotype group (1729 +/- 907 microg) compared with *1a wild-type control subjects (2974 +/- 1590 microg) (P =.049). CONCLUSION: There was a significant effect of tested OATP-C variant haplotypes on pravastatin disposition. Whereas *5 expression delayed the hepatocellular uptake of pravastatin, *1b expression seemed to accelerate OATP-C-dependent uptake of the drug.
Authors:
Jessica Mwinyi; Andreas Johne; Steffen Bauer; Ivar Roots; Thomas Gerloff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  75     ISSN:  0009-9236     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  2004 May 
Date Detail:
Created Date:  2004-04-29     Completed Date:  2004-05-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  415-21     Citation Subset:  AIM; IM    
Affiliation:
Institute of Clinical Pharmacology, Humboldt University, Berlin, Germany.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Adult
Area Under Curve
Genotype
Haplotypes
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage,  pharmacokinetics*,  urine
Male
Organic Anion Transport Polypeptide C / genetics*
Pharmacogenetics
Pravastatin / administration & dosage,  pharmacokinetics*,  urine
Chemical
Reg. No./Substance:
0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Organic Anion Transport Polypeptide C; 81093-37-0/Pravastatin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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