We have studied the time course of the concentrations of nortriptyline (NT) in whole rat blood in vivo after intravenous, intraperitoneal and oral administration and the hepatic uptake and metabolism of this drug in isolated perfused rat livers using a non-recirculating perfusion medium. The clearance of NT from whole blood in vivo was close to the rat liver blood flow reported in the literature, and it was similar in both untreated and phenobarbital (80 mg/kg i.p. for 4 days) treated rats. At inflow concentrations of NT ranging between 88–500 ng/ml the hepatic extraction ratio was close to unity in the perfused liver, and the clearance thus equalled the flow of the perfusion medium through this organ. The reason for this was that NT was rapidly taken up and metabolized by the liver. We hypothesize that this efficient hepatic extraction of NT, associated with a rapid oxidation, may be related to the high lipid solubility and unusually high affinity to liver microsomal cytochrome P-450 of this drug. We also suggest that two non-enzymatic factors, namely tissue distribution and hepatic blood flow, to a large extent determine the rate of metabolic elimination of NT in rats. Finally, our data show that NT has a low availability in rats after oral and intraperitoneal administration. This should be considered when elucidating the pharmacodynamics and pharmacokinetics of tricyclic anti-depressant drugs.