Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics.
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.
Katz
David A
DA
Department of Pharmacogenetics, Abbott Laboratories, Abbott Park, IL 60064, USA. david.katz@abbott.com
Carr
Robert
R
Grimm
David R
DR
Xiong
Hao
H
Holley-Shanks
Rhonda
R
Mueller
Toby
T
Leake
Brenda
B
Wang
Qiang
Q
Han
Lixin
L
Wang
Perry G
PG
Edeki
Timi
T
Sahelijo
Leonardo
L
Doan
Thao
T
Allen
Andrew
A
Spear
Brian B
BB
Kim
Richard B
RB
D000328:Adult; D000483:Alleles; D000077868:Atrasentan; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D014162:Transfection
D002352:Carrier Proteins; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011759:Pyrrolidines; C503999:SLCO1B1 protein, human; D000077868:Atrasentan