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Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2006 Mar; Vol. 79 (3), pp. 186-96. Date of Electronic Publication: 2006 Feb 17. - Publication Year :
- 2006
-
Abstract
- Objective: Our objective was to learn whether genetic polymorphisms of metabolic enzymes or transport proteins provide a mechanistic understanding of the in vivo disposition of atrasentan, a selective endothelin A receptor antagonist.<br />Methods: Atrasentan uptake was measured in HeLa cells transfected to express major alleles of organic anion transporting polypeptide 1B1 (OATP1B1). The results were used to classify individuals as extensive, intermediate, or poor OATP1B1 transporters according to their SLCO1B1 genotypes. Analysis of covariance including genotype, study, age, weight, sex, and ethnicity was used to identify factors influencing atrasentan single-dose (n = 44) and steady-state (n = 38) pharmacokinetic parameters. Genotypes for cytochrome P450 3A5, uridine diphosphate-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B15, adenosine triphosphate-binding cassette subfamily B (ABCB) 1, solute carrier organic anion transporter (SLCO) 1B1, and solute carrier family 22 (SLC22) A2 were each assessed.<br />Results: Single-dose atrasentan exposure (P = .0244), steady-state atrasentan exposure (P = .0108), and maximum postdose plasma concentration (P = .0002) were associated with OATP1B1 activity classified by SLCO1B1 genotype. No other tested genotypes were observed to be associated with both single-dose and steady-state atrasentan pharmacokinetics.<br />Conclusions: OATP1B1 is a meaningful factor for atrasentan disposition. Individuals may be classified as having extensive, intermediate, or poor OATP1B1 transport phenotypes according to SLCO1B1 genotypes. Increased exposures of OATP1B1 substrates might be expected in individuals who have the poor transporter phenotype or are treated with an OATP1B1 inhibitor.
- Subjects :
- Adult
Alleles
Atrasentan
Carrier Proteins genetics
Carrier Proteins metabolism
Female
Genotype
HeLa Cells
Humans
Liver-Specific Organic Anion Transporter 1
Male
Middle Aged
Organic Anion Transporters physiology
Phenotype
Transfection
Organic Anion Transporters genetics
Pyrrolidines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0009-9236
- Volume :
- 79
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 16513443
- Full Text :
- https://doi.org/10.1016/j.clpt.2005.11.003