NEW HEPATOCELLULAR DIFFUSION-MODEL FOR ANALYSIS OF HEPATOBILIARY TRANSPORT PROCESSES OF DRUGS

A new hepatocellular diffusion model was developed to kinetically eval uate the hepatobiliary transport processes of drugs in the perfusion s ystem, based on the physiological structure of the liver. Since the eq uations describing the hepatocellular diffusion phenomena were derived as image forms in the Laplace domain, the fast inverse Laplace transf orm (FILT) was adopted to manipulate the image equations. Cefixime and cefpiramide were selected as model drugs. The concentrations in the p erfusate and the excreted amounts into the bile were simultaneously me asured at appropriate intervals after the rapid administration of each drug into the portal vein. The hepatocellular diffusion model was fit ted to the biliary excretion profiles from the rat livers, by means of a nonlinear least squares program, MULTI(FILT). According to this mod el, the hepatobiliary transport process of drug is kinetically separat ed into three steps, that is, the diffusion into and through the hepat ocytes, the transfer from the hepatocytes into the bile canaliculi, an d the movement through the bile canaliculi to the outlet of bile duct. These steps are characterized by the diffusion rate constant through hepatocytes (k(dif)), the permeability rate constant into the bile can aliculi (k(bmc)) and the transit time through the bile canaliculi to t he outlet of bile duct ((t) over bar(can)), respectively. It was demon strated the kdif of cefixime (0.023 min(-1)) was significantly smaller than that of cefpiramide (0.044 min(-1)), while the differences in k( bmc) and (t) over bar(can) were not obvious between cefixine and cepfi ramide. K-bmc and (t) over bar(can) of both drugs were about 1.2 min(- 1) and about 1.0 min, respectively. These parameters were correlated t o the excretion ratio into the bile (F-bile) and the mean transit time from the sinusoid through the hepatocytes to the outlet of bile duct ((t) over bar(bile)).