An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

Bowman, Christine M.; Benet, Leslie Z.

doi:10.1016/j.ejps.2018.08.008

Cited by 78 publications

(54 citation statements)

References 121 publications

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“…However, for the two additional very low albumin concentrations, results were preferentially consistent with the well-stirred model. Recent studies in the Poulin, Sugiyama and Benet laboratories with hepatocytes report markedly improved IVIVE predictability in the presence of albumin than in its absence (Bowman and Benet, 2018;Poulin and Haddad, 2018;Kim et al, 2019). This could also explain the differences seen by Roberts et al (1990) with zero protein concentration for taurocholate.…”

Section: Vascular Dispersion and Axial Tissue Diffusionmentioning

confidence: 97%

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

2020

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In reviewing previously published isolated perfused rat liver studies, we find no experimental data for high clearance metabolized drugs that reasonably or unambiguously supports preference for the dispersion and parallel tube models versus the well-stirred model of organ elimination when only entering and exiting drug concentrations are available. It is likely that the investigators cited here may have been influenced by: 1) the unphysiologic aspects of the well-stirred model, which may have led them to undervalue the studies that directly test the various hepatic disposition models for high clearance drugs (for which model differences are the greatest); 2) experimental assumptions made in the last century that are no longer valid today, related to the predictability of in vivo outcomes from in vitro measures of drug elimination and the influence of albumin in hepatic drug uptake; and 3) a lack of critical review of previously reported experimental studies, resulting in inappropriate interpretation of the available experimental data. The number of papers investigating the theoretical aspects of the dispersion, parallel tube and well-stirred models of hepatic elimination greatly outnumber the papers that actually examine the experimental evidence available to substantiate these models. When all experimental studies that measure organ elimination using entering and exiting drug concentrations at steady state are critically reviewed, the simple but unphysiologic well-stirred model is the only model that can describe all trustworthy published available data. SIGNIFICANCE STATEMENT Although the dispersion model of hepatic elimination more adequately reflects physiologic reality, there are no convincing experimental data that unambiguously favor this model. The well-stirred model can describe all well-designed perfusion studies with high clearance drugs and non-drug substrates, but the field has not recognized this due to hesitation to accept a non-physiologic model and flawed attempts to utilize IVIVE approaches.

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Section: Vascular Dispersion and Axial Tissue Diffusionmentioning

confidence: 97%

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

2020

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“…Despite the high protein binding of carprofen, eventual accumulation into the lipid matrix occurs due to the protein‐bound and unbound fraction existing in equilibrium. As the unbound fraction becomes taken‐up by the lipid matrix, the unbound fraction will be replaced to maintain this equilibrium . High concentrations of carprofen in plasma after treatment with lipids are likely due to the attraction to the lipids in plasma and a decreased distribution to the tissue compartment.…”

Section: Discussionmentioning

confidence: 99%

Use of intravenous lipid therapy in a cat with carprofen overdose

Chumbler

Schildt

Mawby

et al. 2020

Clinical Case Reports

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“…2). Averaged over the six trials, there were 1931 vHPCs in the Periportal band (dPV = 4-7), 1271 in the Mid-zonal band (dPV = [11][12][13][14], and 540 in the Pericentral band (dCV = 0-3). The average amount of vCompound-1 within a vHPC was proportional to Exposure Rates.…”

Section: Resultsmentioning

confidence: 99%

“…A core assumption of IVIVE methods is that it is the unbound drug adjacent to HPCs that enters HPCs, thus becoming available to the intra-HPC processes responsible for drug metabolism and excretion. The unbound fraction of drug (fu) is an important variable in IVIVE predictions [13]. In the absence of active transport, researchers typically assume that the amount of compound within HPCs is directly proportional to the unbound fraction of drug in media or plasma [14].…”

Section: Introductionmentioning

confidence: 99%

“…Together the two regions account for 100% of vHPCs. From left to right, measures are recorded within three bands: Periportal (dPV = 4-7), Mid-zonal (dPV =[11][12][13][14], and Pericentral (dCV = 0-3). The mean vHPC counts at an average distance of dPV = 0-3 are smaller than the count at dPV = 4 because a few SSes in Layer 1 have MC sampled lengths of only 2-3 grid spaces.…”

mentioning

confidence: 99%

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

Krishnan

Dutta

Smith

et al.

EPiC Series in Computing

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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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An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation

Cited by 78 publications

References 121 publications

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

Are There Any Experimental Perfusion Data that Preferentially Support the Dispersion and Parallel-Tube Models over the Well-Stirred Model of Organ Elimination?

Use of intravenous lipid therapy in a cat with carprofen overdose

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

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