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A recirculated perfusion system was used to investigate the metabolism of tramadol, an analgesic agent, in the isolated perfused rat liver. Tramadol was added to the perfusion medium at a concentration of 300 ng/ml, and the perfusate samples were collected for 180 min. The concentration of tramadol and its three main metabolites O-desmethyltramadol (M1) and N-desmethyltramadol (M2) and N,O-didesmethyltramadol (M5) were determined in perfusate samples by a rapid HPLC method. All through the study, the phase I metabolism of tramadol led to the formation of M1 metabolite from early sampling points while M5 metabolite was detectable after 50 min in 6 out of 10 perfused livers and the M2 metabolite was not detectable in any experiment. The kinetic parameters of tramadol and two detectable metabolites (M1 and M5) were then calculated in perfusate samples. The tramadol concentration decreased from 297.8 to 159.6 ng/ml, with a mean half-life of 232.4 min and a hepatic clearance of 0.73 ml/min. After 180 min, the mean concentration of M1 reached 59.5 ng/ml, resulting in a metabolic ratio of 16%, while the formation of M5 metabolite continued to a mean concentration of 14.6 ng/ml resulting in a metabolic ratio of 2% using AUC(0−180min). Copyright © 2008 John Wiley & Sons, Ltd.