The Metabolism and Disposition of ¹⁴C-Indolidan, a Potent and Orally Active Cardiotonic Agent, in Four Species of Laboratory Animals

Abstract

1. The metabolism and disposition of ¹⁴C-indolidan, a potent, orally-active positive inotrope with vasodilator properties, has been studied after single dose oral administration to rats, mice, dogs and monkeys.

2. Excretion of ¹⁴C in all 4 species was mostly via the urine, largely as parent drug together with two other major metabolites.

3. The two metabolites have been isolated and identified, by mass spectroscopy and ¹H-n.m.r., as a dehydro-compound, with a double bond in the pyridazanone ring, and a hydroxylated derivative of the parent drug.

4. Plasma t_1/2 values, based on ¹⁴C, were 14 h in dog, 5 h in mouse and 8 h in monkey. Plasma t_1/2 of parent drug, by h.p.l.c. was 10 h in dog, approx. 5h in rodents, and 8h in monkeys.

5. Tissue distribution in rats showed no accumulation in any tissue; ¹⁴C concn. in all tissues were indistinguishable from background 48 h after dosage. ¹⁴C peaked at 6–8 h for most tissues but in blood and plasma, ¹⁴C was maximal 1 h after dosing.