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Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics
Author(s) -
Katz David A.,
Carr Robert,
Grimm David R.,
Xiong Hao,
HolleyShanks Rhonda,
Mueller Toby,
Leake Brenda,
Wang Qiang,
Han Lixin,
Wang Perry G.,
Edeki Timi,
Sahelijo Leonardo,
Doan Thao,
Allen Andrew,
Spear Brian B.,
Kim Richard B.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.11.003
Subject(s) - slco1b1 , pharmacokinetics , pharmacology , organic anion transporting polypeptide , atp binding cassette transporter , genotype , chemistry , solute carrier family , organic anion transporter 1 , pharmacogenetics , transporter , biology , biochemistry , gene
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. Clinical Pharmacology & Therapeutics (2006) 79 , 186–196; doi: 10.1016/j.clpt.2005.11.003