Studies on the metabolic disposition of ciramadol, a new orally effective analgesic, have been conducted in the rhesus monkey and male rat. The drug is well absorbed but undergoes extensive presystemic metabolism when given by the intragastric route (1 mg/kg) to rhesus monkeys. Maximum concentrations in plasma do not exceed 4 ng/ml. The major transformation occurs by glucuronidation and leads to two metabolites, and aryl O- and an alicyclic O-glucuronide. Phase I transformations are apparently minor and include N-demethylation, formation of benzoxazinyl metabolites from the reaction of endogenous acetaldehyde and formaldehyde with N-desmethylciramadol, and oxidation of the alicyclic and aromatic rings. Mass-spectrometric analyses of the isolated glucuronides and the minor phase I metabolites have been employed for structural assignments. Excretion of the intragastric dose occurs predominantly by the renal route. When given intramuscularly (1 mg/kg), concentrations of ciramadol peak at 1150 ng/ml by 0.5 hr after medication and decline rapidly to less than 7 ng/ml by 8 hr. Approximately 10% of the dose is excreted as unchanged ciramadol after im dosing. In male rats, the drug is absorbed rapidly after single 1-mg/kg intragastric doses and is taken up notably by liver, lung, kidney and spleen. Unlike its disposition in rhesus monkeys, ciramadol is present in plasma and excreted into urine mainly in the unconjugated form. Concentrations of drug in rat plasma are higher than those in rhesus monkey plasma, suggesting a smaller first-pass effect in the rat.