The metabolism of [14C]rimantadine hydrochloride in rats and dogs

AC Loh, AJ Szuna, TH Williams, GJ Sasso and FJ Leinweber

Department of Drug Metabolism, Hoffman-La Roche Inc., Nutley, NJ 07110- 1199.

Metabolism and route of excretion of [14C]rimantadine hydrochloride was studied in male rats after single po (60 mg/kg) and iv doses (15 mg/kg) and in male dogs (5 or 10 mg/kg po and 5 mg/kg iv). Total 14C excretion in urine (po and iv) in both species reached 81-87% of the dose in 96 hr. Rimantadine was excreted in rats free (1.0% po, 1.7% iv) and conjugated (0.8% of the dose, po and iv, both in 24 hr) and in dogs, free (2.6% po, 3.0% iv) and conjugated (6.4% po, 7.7% iv, both in 48 hr). In both species, rimantadine metabolism is essentially independent of the route of administration. In rats and dogs, m-hydroxyrimantadine (mostly unconjugated) was the major metabolite, 22% (po) and 24% (iv), and 27% (po) and 21% (iv), respectively. Rats, but not dogs, excreted trans-p-hydroxyrimantadine (23.5% and 25.2%, po and iv, free plus conjugated). An oxidative pathway in dogs produced the m- and p- hydroxylated analogs with a hydroxyl in place of the amino group (3.7% and 5.7% of the dose, both conjugated). A p-hydroxylated compound with a nitro group in place of the amino group may have originated from an N- hydroxy metabolite by spontaneous oxidation during isolation. Comparison of total 14C excretion, in rats (81%, po; 82%, iv) and dogs (81%, po; 84%, iv) after po and iv administration after 96 hr indicates good absorption of rimantadine.

Volume 19, Issue 2, pp. 381-387, 03/01/1991
Copyright © 1991 by American Society for Pharmacology and Experimental Therapeutics