In vitro and in vivo studies on the metabolism of tirofiban.
Tirofiban hydrochloride [L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebutyl)] monohydrochloride, is a potent and specific fibrinogen receptor antagonist. Radiolabeled tirofiban was synthesized with either (3)H-label incorporated into the phenyl ring of the tyrosinyl residue or (14)C-label in the butane sulfonyl moiety. Neither human liver microsomes nor liver slices metabolized [(14)C]tirofiban. However, male rat liver microsomes converted a limited amount of the substrate to a more polar metabolite (I) and a relatively less polar metabolite (II). The formation of I was sex dependent and resulted from an O-dealkylation reaction catalyzed by CYP3A2. Metabolite II was identified as a 2-piperidone analog of tirofiban. There was no evidence for Phase II biotransformation of tirofiban by microsomes fortified with uridine-5'-diphospho-alpha-D-glucuronic acid. After a 1 mg/kg i.v. dose of [(14)C]tirofiban, recoveries of radioactivity in rat urine and bile were 23 and 73%, respectively. Metabolite I and unchanged tirofiban represented 70 and 30% of the urinary radioactivity, respectively. Tirofiban represented >90% of the biliary radioactivity. At least three minor biliary metabolites represented the remainder of the radioactivity. One of them was identified as I. Another was identified as II. When dogs received 1 mg/kg i.v. of [(3)H]tirofiban, most of the radioactivity was recovered in the feces as unchanged tirofiban. The plasma half-life of tirofiban was short in both rats and dogs, and tirofiban was not concentrated in tissues other than those of the vasculature and excretory organs.
Vickers
S
S
Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA. stanley_vickers@merck.com
Theoharides
A D
AD
Arison
B
B
Balani
S K
SK
Cui
D
D
Duncan
C A
CA
Ellis
J D
JD
Gorham
L M
LM
Polsky
S L
SL
Prueksaritanont
T
T
Ramjit
H G
HG
Slaughter
D E
DE
Vyas
K P
KP
D000818:Animals; D001646:Bile / Q000378:metabolism; D004285:Dogs; D005243:Feces; D005260:Female; D005343:Fibrinolytic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006207:Half-Life; D006801:Humans; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077466:Tirofiban; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
D005343:Fibrinolytic Agents; D014443:Tyrosine; D000077466:Tirofiban