Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog.
1. The metabolic fate of 14C-benzarone in the rat and dog has been compared to that in human subjects. An oral dose was well-absorbed in all three species. However, the 14C excretion patterns differed: humans (100 mg) excreted means of 73 and 19% dose in the urine and faeces respectively, whereas the rat (2 mg/kg) and dog (0.5 mg/kg) excreted greater than 80% in the faeces, mostly during the first 48 h. 2. Much of the faecal 14C was attributable to 14C excreted in the bile which amounted to 59% in the 7 h bile collected from an intravenously dosed dog, and a mean of 72% in the 24 h bile of orally dosed rats. Enterohepatic circulation of 14C was demonstrated in rats. 3. Total 14C in human plasma reached peak concentrations between 1-2 h and declined relatively rapidly, to about 10% of this value within 24 h. Unchanged benzarone was not detected in plasma (less than 25 ng/ml), even after a 400 mg dose, but conjugated benzarone was--accounting for about 10% of the peak concentration of 14C. In the dog, by contrast, conjugated benzarone accounted for about 50% of the peak concentration of 14C of 0.96 microgram equiv./ml at 1 h. The extent of binding of benzarone to human plasma proteins (greater than 99%; in vitro was slightly greater than that (greater than 96%) of total 14C (ex vivo, representing metabolites). 4. Examination of metabolite profiles by h.p.l.c. suggested that in the rat and dog, at least 70% absorbed dose was eliminated by direct conjugation, whereas in humans at least 70% was hydroxylated before conjugation, mainly with glucuronic acid. Hydroxylation occurred in the benzofuran ring and/or the ethyl side-chain. The principal urinary metabolite in humans was the conjugate(s) of the 1-hydroxylated ethyl side-chain derivative (mean 26% dose).
Wood
S G
SG
Department of Metabolism and Pharmacokinetics, Huntingdon Research Centre, UK.
John
B A
BA
Chasseaud
L F
LF
Bonn
R
R
Grote
H
H
Sandrock
K
K
Darragh
A
A
Lambe
R F
RF
D000328:Adult; D000818:Animals; D001553:Benzbromarone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D001572:Benzofurans / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000032:analysis; D005343:Fibrinolytic Agents / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007408:Intestinal Absorption; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D001572:Benzofurans; D001798:Blood Proteins; D005343:Fibrinolytic Agents; C004528:benzarone; D001553:Benzbromarone