scholarly journals Extrapolation of In Vivo Hepatic Clearance from In Vitro Uptake Clearance by Suspended Human Hepatocytes for Anionic Drugs with High Binding to Human Albumin: Improvement of In Vitro-to-In Vivo Extrapolation by Considering the “Albumin-Mediated” Hepatic Uptake Mechanism on the Basis of the “Facilitated-Dissociation Model”

2018 ◽  
Vol 47 (2) ◽  
pp. 94-103 ◽  
Author(s):  
Soo-Jin Kim ◽  
Kyeong-Ryoon Lee ◽  
Seiji Miyauchi ◽  
Yuichi Sugiyama
Keyword(s):  
Hepatic Clearance ◽  
Hepatic Uptake ◽  
Human Albumin ◽  
Human Hepatocytes ◽  
Uptake Mechanism ◽  
Dissociation Model ◽  
Anionic Drugs ◽  
In Vivo Extrapolation

scholarly journals Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

10.29007/t4kv ◽  
2020 ◽  
Author(s):  
Lopamudra Dutta ◽  
Preethi Krishnan ◽  
Andrew Smith ◽  
Ryan Kennedy ◽  
Glen Ropella ◽  
...  
Keyword(s):  
Hepatic Clearance ◽  
Intrinsic Clearance ◽  
Quasi Steady State ◽  
Exposure Rate ◽  
Virtual Experiments ◽  
Mitigating Factors ◽  
Virtual Mouse ◽  
In Vivo Extrapolation

An improved understanding of in vivo ⇔ in vitro changes is crucial in identifying and mitigating factors contributing to in vitro–in vivo extrapolation (IVIVE) inaccuracies in predicting the hepatic clearance of substances. We argue that a model mechanism-based virtual culture (vCulture) ⇔ virtual mouse (vMouse) (or vRat or vHuman) experiment approach can identify factors contributing to IVIVE disconnects. Doing so depends on having evidence that six Translational Requirements have been achieved. We cite evidence that the first four have been achieved. The fifth Requirement is that differences in measures of vCompound disposition between vCulture and vMouse are attributable solely to the micro-architectural, physiomimetic features, and uncertainties built into the vLiver and vMouse but are absent from the vCulture. The objective of this work is to first improve on a vCulture architecture used previously and then use results of virtual experiments to verify that its use enables the fifth Translational Requirement to be achieved. We employ two different idealized vCompounds, which map to highly permeable real compounds at the extreme ends of the intrinsic clearance spectrum. Virtual intrinsic clearance = Exposure rate per vHPC. At quasi-steady state, results for vCompound-1 are independent of the dosing rate. The average per-vHPC Exposure rates (taken over the whole vLiver in vMouse experiments) are the same (within the variance of the Experiments) as those in vCulture. However, they are location dependent within the vLiver. For vCompound-2, there are dosing rate differences and average per-vHPC Exposure rates within the vLiver are also location dependent. When we account for dosing rate differences, we see again that average per-vHPC Exposure rates averaged over the whole vLiver in vMouse experiments are the same as those in vCulture. Thus, the differences in per vHPC Exposure rate within the vLiver for both vCompounds are attributable solely to the micro-architectural and physiomimetic features built into the vLiver and vMouse but are absent from the vCulture. The results verify that the fifth Translational Requirement has been achieved.

Sign in / Sign up

Export Citation Format

Share Document