Pharmacokinetics of levonantradol in laboratory animals and man

Levonantradol exhibits potent analgetic activity in standard animal tests and appears not to act directly at opiate receptors. It is currently in clinical trials as an analgesic and antiemetic. The pharmacokinetic behavior of levonantradol, administered orally or intramuscularly, has been investigated in man at dose levels of 0.25 to 3.0 mg and in animals at 0.03 to 10 mg/kg, using a specific HPLC/electrochemical assay. Only desacetyllevonantradol is detected in plasma, due to rapid in vivo deacetylation of levonantradol. In man, at the various doses tested, plasma concentrations of desacetyllevonantradol range from less than 5 to 51 ng/ml. Comparable plasma levels and clinical activity occur at nearly identical doses after oral and intramuscular dosing, suggesting good oral absorption in man. In animals, desacetyllevonantradol has a time of peak concentration of 1 to 2 hours and an elimination half-life of 1 to 2 hours. In animals, a tenfold higher oral dose is needed to achieve the same plasma drug levels as that after an intramuscular dose, suggesting extensive first-pass metabolism following oral administration. Little or no evidence for drug accumulation and sex differences in plasma concentrations of desacetyllevonantradol is noted during chronic intramuscular dosing in laboratory animals.