Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics.
Clin Pharmacol Ther
; 79(3): 186-96, 2006 Mar.
Article
en En
| MEDLINE
| ID: mdl-16513443
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.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.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.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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirrolidinas
/
Transportadores de Anión Orgánico
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Clin Pharmacol Ther
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA