Dual effects of rifampin on the pharmacokinetics of atrasentan.
The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open-label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half-life by 77% (P<.05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide-mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.
Xiong
Hao
H
Department of Clinical Pharmacokinetics, Abbott Laboratories, 100 Abbott Park Road, Dept. R4PK, AP13A-3, Abbott Park, IL 60064-6104, USA. hao.xiong@abbott.com
Carr
Robert A
RA
Locke
Charles S
CS
Katz
David A
DA
Achari
Ramanuj
R
Doan
Thao T
TT
Wang
Perry
P
Jankowski
James R
JR
Sleep
Darryl J
DJ
D000328:Adult; D019540:Area Under Curve; D000077868:Atrasentan; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004357:Drug Synergism; D065130:Endothelin A Receptor Antagonists; D004790:Enzyme Induction; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077868:Atrasentan; D012293:Rifampin