Evaluation of ammonia and lidocaine clearance, and galactose elimination capacity of xenoperfused pig livers using a pharmacokinetic analysis.

Abstract

We introduced the pharmacokinetic method into the functional evaluation of xenogeneic extracorporeal liver perfusion as an artificial liver assist device, and examined the influence of xenogeneic humoral injury on the metabolic function of xenoperfused pig livers. Isolated pig livers were perfused with fresh porcine blood (group 1; n=5) or fresh human blood (group 2; n=5) for 9 hr. Clearance (CL) of ammonia and lidocaine, and galactose elimination capacity (Vmax) were determined at three points during the perfusion using a one-compartment pharmacokinetic model. Concentrations of ammonia and lidocaine decreased exponentially and those of galactose decreased linearly after a bolus injection in both groups. A one-compartment model provided satisfactory curve fittings for these test substances. No decreases of ammonia CL, lidocaine CL, or galactose Vmax were observed until 9 hr in either group. No differences were observed between the two groups with respect to these metabolic functions. In group 1, only slight interlobular edema was observed at 9 hr. In group 2, membrane attack complex was diffusely deposited at 3 hr and severe interlobular damage was histologically observed at 9 hr, although hepatocellular damage was minimal even at 9 hr. Alpha glutathione S-transferase and mitochondrial aspartate aminotransferase were comparable between the two groups. Pharmacokinetic analysis allowed the evaluation of ammonia CL, lidocaine CL, and galactose Vmax of the perfused pig livers. Despite xenogeneic humoral injuries, the xenoperfused livers maintained these metabolic functions at the same levels as the alloperfused livers for 9 hr.