New hepatocellular diffusion model for analysis of hepatobiliary transport processes of drugs |
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Authors: | Hiroyuki Yasui Kiyoshi Yamaoka Terumichi Nakagawa |
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Institution: | (1) Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, 606-01 Kyoto, Japan |
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Abstract: | 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 (
), respectively. It was demonstrated that kdif of cefixime (0.023min1) was significantly smaller than that of cefpiramide (0.044 min1), while the differences in kbmc and
were not obvious between cefixime and cefpiramide. kbmc and
of both drugs were about 1.2 min1 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 (
). |
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Keywords: | rat liver perfusion hepatobiliary transport biliary excretion hepatocellular diffusion model FILT MULTI(FILT) cefixime cefpiramide |
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