Nantradol hydrochloride: pharmacokinetics and behavioral effects after acute and chronic treatment

Studies with [3H]nantradol hydrochloride indicate that nantradol is extensively metabolized after oral administration. By using a liquid chromatography assay with electrochemical detection, specific for both nantradol and desacetylnantradol, only desacetylnantradol is detected in plasma of rats and dogs dosed with nantradol. In animal analgetic tests, desacetylnantradol exhibits activity at least equal to nantradol. Together, these findings and additional in vitro enzymatic studies suggest that desacetylnantradol is the analgetically active species in vivo. In rats and dogs, desacetylnantradol has an apparent half-life of about 2 hr. No evidence for drug accumulation or alteration of drug metabolizing enzymes is noted from desacetylnantradol plasma level determinations during 90 days of oral and 14 days of i.m. dosing in dogs or rats at doses of 0.125 to 0.5 mg/kg i.m. and 2.5 to 10 mg/kg p.o. The static ataxia test in dogs was used to assess behavioral tolerance after chronic dosing (90 days); unlike delta 9-tetrahydrocannabinol only modest tolerance development is observed.