Liver Fibrosis Impairs Hepatic Pharmacokinetics of Liver Transplant Drugs in the Rat Model

Abstract

  This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, furosemide) given to patients undergoing liver transplantation before surgery in CCl₄-induced fibrotic perfused rat livers and compare to that in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single pass perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl₄ treated rats compared to controls (p < 0.05). The extraction ratio (E) for all drugs were significantly lower (p < 0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance (CL_int) and permeability surface area product (PS). In addition, other than for furosemide, the mean transit times for all drugs was significantly longer (p < 0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to that previously found for another group of drugs.