NDLI: Quantitative Evaluation of Capacity-Limited Hepatobiliary Transport Based on Hepatocellular Diffusion Model by MULTI(FEM)

Content Provider	Springer Nature Link
Author	Higashimori, Mitsuo Yamaoka, Kiyoshi Fujitani, Sumiaki Nakagawa, Terumichi
Copyright Year	2001
Abstract	The dose-dependency of hepatic uptake and hepatobiliary transport of a drug was evaluated by means of a nonlinear least square program incorporating the finite element method, MULTI(FEM). A perfusion experiment using isolated rat livers following a pulse input (i.e., under non-steady-state conditions) was performed at three dose levels of cefpiramide as a model drug. The hepatic extraction ratio (E$_{H}$) of cefpiramide decreased with an increase in dose, which demonstrates that the hepatic uptake is capacity-limited. The outflow time-profiles from the liver were represented by a two-compartment dispersion model with central Michaelis–Menten elimination, and the maximal elimination rate per central compartment volume (V$_{max}$) and the Michaelis constant (K$_{m}$) were estimated to be 1420 μg/ml/min and 235 μg/ml, respectively. The biliary mean transit time $$({\bar t}_{bile} )$$ increased slightly with an increase in dose. The hepatocellular diffusion model under non-steady-state conditions considering nonlinear transport across the bile canalicular membrane was adopted to evaluate dose-dependency in the biliary excretion of cefpiramide. The maximal penetration velocity across the bile canalicular membrane per liver $$({V}_{max}^{bcm} )$$ and the affinity constant of penetration across the bile canalicular membrane $$({k}_{m}^{bcm} = {\text{K}}_{\text{m}}^{bcm} {\text{A}}_{\text{H}} {\text{L}})$$ were estimated to be 40.1 μg/min and 123 μg, respectively. Considering that the volume of a rat liver (A$_{H}$.L) is approximately 10 ml, the Michaelis constant of penetration (k m bmc ), which is an apparent parameter, was estimated to be approximately 12.3 μg/ml. In conclusion, MULTI(FEM) is useful for evaluation of capacity-limited local disposition.
Starting Page	415
Ending Page	444
Page Count	30
File Format	PDF
ISSN	1567567X
Journal	Journal of Pharmacokinetics and Pharmacodynamics
Volume Number	28
Issue Number	5
e-ISSN	15738744
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2001-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Veterinary Medicine Biochemistry Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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