Disposition of the aromatase inhibitor LY56110 and associated induction and inhibition studies in rats, dogs, and monkeys

Compound LY56110 was well absorbed but slowly excreted in the rat, dog, and monkey. Oral administration of 5 mg/kg of [14C]LY56110 (5-bis(4-chlorophenyl)methylpyrimidine) to the rat, monkey, and dog resulted in a total excretion of 68, 65, and 30% of the radioactivity within 5 days, respectively. Very low urinary excretion was observed in the rat and dog (2%), with fecal excretion being the predominant mode of elimination in all three species. The plasma radioactivity half-life was 49, 41, and greater than 100 hr in the rat, monkey, and dog, respectively. The plasma half-life of parent compound was 18 hr in the rat and 10 hr in the dog. LY56110 accounted for only 25, 12, and 1% of the plasma radioactivity area under the curve in the rat, dog, and monkey, respectively. High levels of radioactivity were observed in the target tissues of fat, adrenals, and ovaries of rats. LY56110 induced hepatic cytochromes b5 and P-450 and cytochrome c reductase in rats after 14 days of oral dosing at 10 mg/kg but not in monkeys after 10 days of oral dosing at 10 mg/kg. The compound was more potent than aminoglutethimide or cimetidine in inhibiting hepatic ethylmorphine and p-nitroanisole demethylase activity in vitro. LY56110 also inhibited ethinamate-induced sleeping time in rats in vivo. The compound induced a reverse type I binding spectrum with rat ovarian microsomes.