1. The effect of albumin on the disposition of morphine and hepatically generated morphine-3-glucuronide (M3G) was investigated in the single-pass rat isolated perfused liver. 2. Using a balanced cross-over design, each of 10 livers was perfused at 30 mL/min with medium containing 2.7 mumol/L morphine in the presence and absence of 10 g/L bovine serum albumin (BSA). 3. Both bile flow rate and hepatic oxygen consumption were significantly higher (P < 0.005) when BSA was present in the perfusion medium, suggestive of a change in the functional performance of the perfused liver. 4. The binding of morphine and M3G was negligible in both BSA-free and -containing perfusate. 5. Outflow perfusate contained both morphine and M3G, while the metabolite but not morphine was found in bile. The recovery of the administered morphine was approximately 100% and was not altered (P > 0.05) by the presence or absence of BSA. 6. The fraction of morphine escaping heptic extraction in the absence of BSA (mean +/- SD; 0.41 +/- 0.14) was not altered significantly (P > 0.05) by the presence of the protein in perfusate (0.35 +/- 0.13), indicating no change in the intrinsic clearance or morphine despite the difference in oxygen consumption. 7. The fraction of hepatically generated M3G excreted in bile was significantly higher (P < 0.005) when BSA was present in the perfusate than when it was not (0.44 +/- 0.14 vs 0.38 +/- 0.16, respectively). 8. The results are consistent with the concept that BSA modifies the ability of solutes, including M3G, to move through the paracellular pathway from the canalicular to the vascular space. 9. It is concluded that because albumin may modify not only the unbound fraction of a ligand in perfusate, but also the functional performance of the liver, care is needed in the interpretation of studies examining the influence of the protein on the hepatic disposition of drugs and their metabolites.