New hepatocellular diffusion model for analysis of hepatobiliary transport processes of drugs.

A new hepatocellular diffusion model was developed to kinetically evaluate the hepatobiliary transport processes of drugs in the perfusion system, based on the physiological structure of the liver. Since the equations describing the hepatocellular diffusion phenomena were derived as image forms in the Laplace domain, the fast inverse Laplace transform (FILT) was adopted to manipulate the image equations. Cefixime and cefpiramide were selected as model drugs. The concentrations in the perfusate and the excreted amounts into the bile were simultaneously measured at appropriate intervals after the rapid administration of each drug into the portal vein. The hepatocellular diffusion model was fitted to the biliary excretion profiles from rat livers, by means of a nonlinear least squares program, MULTI(FILT). According to this model, the hepatobiliary transport process of drug is kinetically separated into three steps, that is, the diffusion into and through the hepatocytes, the transfer from the hepatocytes into the bile canaliculi, and the movement through the bile canaliculi to the outlet of bile duct. These steps are characterized by the diffusion rate constant through hepatocytes (kdif), the permeability rate constant into the bile canaliculi (kbmc) and the transit time through the bile canaliculi to the outlet of bile duct (tcan), respectively. It was demonstrated that kdif of cefixime (0.023 min-1) was significantly smaller than that of cefpiramide (0.044 min-1), while the differences in kbmc and tcan were not obvious between cefixime and cefpiramide. kbmc and tcan of both drugs were about 1.2 min-1 and about 1.0 min, respectively. These parameters were correlated to the excretion ratio into the bile (Fbile) and the mean transit time from the sinusoid through the hepatocytes to the outlet of bile duct (tbile).