Metabolic fate of the thrombolytic agent benzarone in man: comparison with the rat and dog

Abstract

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 > 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 (< 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 μg equiv./ml at 1 h. The extent of binding of benzarone to human plasma proteins (> 99%; in vitro was slightly greater than that (> 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).