The disposition of prasugrel, a novel thienopyridine, in humans.
Prasugrel, a prodrug, is a novel and potent inhibitor of platelet aggregation in vivo. The metabolism of prasugrel and the elimination and pharmacokinetics of its active metabolite, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid (R-138727), three inactive metabolites, and radioactivity were determined in five healthy male subjects after a single 15-mg (100 microCi) p.o. dose of [(14)C]prasugrel. Prasugrel was rapidly absorbed, and maximum plasma concentrations of radioactivity and R-138727 were achieved in 30 min, indicating rapid formation of R-138727. Prasugrel was extensively metabolized in humans, first by hydrolysis to a thiolactone, followed by ring opening to form R-138727, which was further metabolized by S-methylation and conjugation with cysteine. Total radioactivity was higher in plasma than in blood, suggesting limited penetration of prasugrel metabolites into red blood cells. Approximately 70% of the dose was excreted in the urine and 25% in the feces.
Farid
Nagy A
NA
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. nafarid@lilly.com
Smith
Richard L
RL
Gillespie
Todd A
TA
Rash
T James
TJ
Blair
Patrick E
PE
Kurihara
Atsushi
A
Goldberg
Mark J
MJ
D000284:Administration, Oral; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007408:Intestinal Absorption; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D000068799:Prasugrel Hydrochloride; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D012016:Reference Values; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
D002250:Carbon Radioisotopes; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D011725:Pyridines; C510685:R-138727; D013876:Thiophenes; C446540:thienopyridine; D000068799:Prasugrel Hydrochloride; D003545:Cysteine