The Universally Unrecognized Assumption in Predicting Drug Clearance and Organ Extraction Ratio

Benet, LZ; Liu, S; Wolfe, Alan R.

doi:10.1002/cpt.802

Cited by 36 publications

(27 citation statements)

References 12 publications

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“…Solving for C out / C in and substituting back into the clearance relationship of Eq. 1, as was done initially by Rowland et al (8) and more recently by Benet et al (1), gives the general Eq. 5.…”

Section: Methodsmentioning

confidence: 75%

“…Following IV dosing where all elimination occurs via the liver

\frac{A U C}{D o s e_{I V}} = \frac{1}{C L_{L i v e r}} = \frac{P S_{i n f, i n t} \cdot f_{u, B} \cdot C L_{H, i n t} + Q_{B} \cdot (C L_{H, i n t} + P S_{e f f, i n t})}{Q_{B} \cdot P S_{i n f, i n t} \cdot f_{u . B} \cdot C L_{H, i n t}}

Following oral dosing, the area under the blood concentration time curve ( AUC ), where clearance is only due to liver elimination, is given by

A U C = F \cdot D o s e_{o r a l} / C L_{L i v e r}

where the bioavailability ( F ) is the product of the fraction of the dose absorbed intact ( F abs ), the fraction of the absorbed dose that gets through the gut membranes into the hepatic portal blood intact ( F G ) and the fraction of unchanged drug in the hepatic portal blood that get through the liver intact ( F H )

F = F_{a b s} \cdot F_{G} \cdot F_{H}

Following the relationship first presented by Rowland (18), F H may be determined as one minus the liver extraction ratio ( ER )

F_{H} = 1 - E R = 1 - \frac{C L_{L i v e r}}{Q_{B}}

We have previously shown (1) that this is a well-stirred model assumption, and that the relationship is only correct for the well-stirred model.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently shown (1) that when organ clearance is calculated as the product of the extraction ratio ( ER ) and the blood flow to the organ ( Q ) as in Eq. 1, this is only consistent with the well-stirred model in pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

et al. 2018

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Purpose: To derive the theoretical basis for the extended clearance model of organ elimination following both oral and IV dosing, and critically analyze the approaches previously taken. Methods: We derived from first principles the theoretical basis for the extended clearance concept of organ elimination following both oral and IV dosing and critically analyzed previous approaches. Results: We point out a number of critical characteristics that have either been misinterpreted or not clearly presented in previously published treatments. First, the extended clearance concept is derived based on the well-stirred model. It is not appropriate to use alternative models of hepatic clearance. In analyzing equations, clearance terms are all intrinsic clearances, not total drug clearances. Flow and protein binding parameters should reflect blood measurements, not plasma values. In calculating the AUCR-factor following oral dosing, the AUC terms do not include flow parameters. We propose that calculations of AUCR may be a more useful approach to evaluate drug-drug and pharmacogenomic interactions than evaluating rate-determining steps. Through analyses of cerivastatin and fluvastatin interactions with cyclosporine we emphasize the need to characterize volume of distribution changes resulting from transporter inhibition/induction that can affect rate constants in PBPK models. Finally, we note that for oral doses, prediction of systemic and intrahepatic drug-drug interactions do not require knowledge of fu,H or Kp,uu for substrates/victims. Conclusions: The extended clearance concept is a powerful tool to evaluate drug-drug interactions, pharmacogenomic and disease state variance but evaluating the AUCR-factor may provide a more valuable approach than characterizing rate-determining steps.

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Section: Methodsmentioning

confidence: 75%

“…Following IV dosing where all elimination occurs via the liver

\frac{A U C}{D o s e_{I V}} = \frac{1}{C L_{L i v e r}} = \frac{P S_{i n f, i n t} \cdot f_{u, B} \cdot C L_{H, i n t} + Q_{B} \cdot (C L_{H, i n t} + P S_{e f f, i n t})}{Q_{B} \cdot P S_{i n f, i n t} \cdot f_{u . B} \cdot C L_{H, i n t}}

Following oral dosing, the area under the blood concentration time curve ( AUC ), where clearance is only due to liver elimination, is given by

A U C = F \cdot D o s e_{o r a l} / C L_{L i v e r}

F = F_{a b s} \cdot F_{G} \cdot F_{H}

Following the relationship first presented by Rowland (18), F H may be determined as one minus the liver extraction ratio ( ER )

F_{H} = 1 - E R = 1 - \frac{C L_{L i v e r}}{Q_{B}}

We have previously shown (1) that this is a well-stirred model assumption, and that the relationship is only correct for the well-stirred model.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

et al. 2018

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“…Our experimental model also shows that fluxes across transporters generate the hepatocyte concentrations over time. Moreover, it enables an independent quantification of hepatocyte concentrations while Benet et al (2018b) highlighted recently the difficulty to obtain such values. Consequently, true biliary intrinsic CLs over time were calculated independently of the hepatocyte uptake.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers

2019

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In the liver, several approaches are used to investigate and predict the complex issue of drug-induced transporter inhibition. These approaches include in vitro assays and pharmacokinetic models that predict how inhibitors modify the systemic and liver concentrations of the victim drugs. Imaging is another approach that shows how inhibitors might alter liver concentrations stronger than systemic concentrations. In perfused rat livers associated with a gamma counter that measures liver concentrations continuously, we previously showed how fluxes across transporters generate the hepatocyte concentrations of two clinical imaging compounds, one with a low extraction ratio [gadobenate dimeglumine (BOPTA)] and one with a high extraction ratio [mebrofenin (MEB)]. BOPTA and MEB are transported by rat organic anion transporting polypeptide and multiple resistance-associated protein 2, which are both inhibited by rifampicin. The aim of the study is to measure how rifampicin modifies the hepatocyte concentrations and membrane clearances of BOPTA and MEB and to determine whether these compounds might be used to investigate transporter-mediated drug-drug interactions in clinical studies. We show that rifampicin coperfusion greatly decreases BOPTA hepatocyte concentrations, but increases those of MEB. Rifampicin strongly decreases BOPTA hepatic clearance. In contrast, rifampicin decreases moderately MEB hepatic clearance and blocks the biliary intrinsic clearance, increasing MEB hepatocyte concentrations. In conclusion, low concentrations prevent the quantification of BOPTA biliary intrinsic clearance, while MEB is a promising imaging probe substrate to evidence transporter-mediated drug-drug interactions when inhibitors act on influx and efflux transporters.

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“…This simple but useful relationship allowed for clearance measurements based only on knowledge of entering and exiting concentrations and organ blood flow. In 2018, Benet et al (2018) maintained that Eq. 1 was only consistent with the well-stirred model of hepatic elimination, since the amount lost at steady-state, QH • (Cin -Cout), was divided by the drug concentration entering the liver (Cin) to obtain CLH, and no other concentrations within the liver were considered in the clearance determination.…”

Section: Introductionmentioning

confidence: 99%

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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The Universally Unrecognized Assumption in Predicting Drug Clearance and Organ Extraction Ratio

Cited by 36 publications

References 12 publications

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers

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

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