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.

In vitro-in vivo extrapolation of hepatic clearance involving active uptake: Theoretical and experimental aspects

Xenobiotica ◽  
2007 ◽  
Vol 37 (10) ◽  
pp. 1090-1109 ◽  
Author(s):  
P. J. H. Webborn ◽  
A. J. Parker ◽  
R. L. Denton ◽  
R. J. Riley
Keyword(s):  
Hepatic Clearance ◽  
Active Uptake ◽  
In Vivo Extrapolation

scholarly journals Exposure Measurements on Biomimetic Lobules Using Virtual Experiments to Help Improve IVIVE

10.29007/hjfc ◽  
2020 ◽  
Author(s):  
Preethi Krishnan ◽  
Lopamudra Dutta ◽  
Andrew Smith ◽  
Glen Ropella ◽  
Ryan Kennedy ◽  
...  
Keyword(s):  
Hepatic Clearance ◽  
Intrinsic Clearance ◽  
Central Vein ◽  
Unbound Fraction ◽  
Hepatic Disposition ◽  
Liver Model ◽  
New Chemical Entities ◽  
Model Drug

The in vitro-in vivo extrapolation (IVIVE) methods used currently to predict the hepatic clearance of new chemical entities are plagued by poorly understood inaccuracies. To begin identifying plausible sources, we challenge two of core hypotheses. Hypothesis-1: the intralobular micro-anatomical organization of hepatocytes (HPCs) can be abstracted away. By accepting that hypothesis, one can assume that intrinsic clearance per HPC is essentially the same in vitro and in vivo, and thus an IVIVE method can employ a simplified liver model, typically the “well-stirred” liver model. Hypothesis-2: when the simplified liver model is the “parallel tube model,” drug concentration decreases exponentially from portal to central vein. When either simplified liver model is used, a core assumption is that intrinsic clearance is directly proportional to the unbound fraction of drug. A barrier to progress has been the fact that it is currently infeasible to challenge the two hypotheses using wet-lab experiments. In this work, we challenge virtual counterparts of the two hypotheses by experimenting on virtual mice in which hepatic disposition and clearance are consequences of concretized model mechanisms that have met several demanding requirements, including the following. The virtual liver’s structure and organization are strongly analogous to those of an actual liver, and the hepatic disposition and clearance of several virtual compounds have achieved quantitative validation targets. We study two virtual compounds. Compound-1 simulates the extreme of low-clearance, highly permeable compounds. Compound-2 simulates a highly permeable compound exhibiting maximum intrinsic clearance. We simulate changes in unbound fraction by changing the probability (pEnter) that a Compound-1 or -2 will enter an adjacent HPC during a simulation cycle. Compound-1 and -2 HPC exposure rates do not decrease from portal to central vein: they increase, and that contradicts both hypotheses. Further, the relationship between exposure rates and pEnter is nonlinear. The insights achieved help explain the frequently reported underprediction of in vivo hepatic clearance values. We suggest that IVIVE methods can be improved by utilizing a liver model that couples a biomimetic representation of intralobular HPC organization with biomimetic representations of intrahepatic disposition dynamics.

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