Hepatic clearance concepts and misconceptions: Why the well-stirred model is still used even though it is not physiologic reality?

Pang, K. Sandy; Han, Yi Rang; Noh, Keumhan; Lee, Ping I.; Rowland, Malcolm

doi:10.1016/j.bcp.2019.07.025

Cited by 54 publications

(57 citation statements)

References 65 publications

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“…Although their performance in estimating F h is similar for many drugs, there is a report that the well-stirred model enormously overestimates the F h in a few drugs with F h lower than 10%, and the dispersion model appeared better at this situation [ 9 ]. The dispersion model assumes the concentration gradient from the capillary inlet to the outlet as in the parallel tube model and free diffusion of solutes along the blood flow axis [ 10 ].…”

Section: Theory and Methods To Predict F Hmentioning

confidence: 99%

Predicting human pharmacokinetics from preclinical data: absorption

Choi

Bae²

2020

Transl Clin Pharmacol

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Predicting the rate and extent of oral absorption of drugs in humans has been a challenging task for new drug researchers. This tutorial reviews in vitro and PBPK methods reported in the past decades that are widely applied to predicting oral absorption in humans. The physicochemical property and permeability (typically obtained using Caco-2 system) data is the first necessity to predict the extent of absorption from the gut lumen to the intestinal epithelium (F a). Intrinsic clearance measured using the human microsome or hepatocytes is also needed to predict the gut (F g) and hepatic (F h) bioavailability. However, there are many issues with the correction of the inter-laboratory variability, hepatic cell membrane permeability, CYP3A4 dependency, etc. The bioavailability is finally calculated as F = F a × F g × F h. Although the rate of absorption differs by micro-environments and locations in the intestine, it may be simply represented by k a. The k a , the first-order absorption rate constant, is predicted from in vitro and in vivo data. However, human PK-predicting software based on these PBPK theories should be carefully used because there are many assumptions and variances. They include differences in laboratory methods, inter-laboratory variances, and theories behind the methods. Thus, the user's knowledge and experiences in PBPK and in vitro methods are necessary for proper human PK prediction.

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Section: Theory and Methods To Predict F Hmentioning

confidence: 99%

Predicting human pharmacokinetics from preclinical data: absorption

Choi

Bae²

2020

Transl Clin Pharmacol

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“…More recently, we have restated that Eq. 1 is not based on the WSM (Rowland and Pang, 2018;Pang et al, 2019). However, Eq.…”

Section: -Ementioning

confidence: 99%

“…Physiologically oriented clearance models that are particularly applied to hepatic elimination have been widely discussed (Roberts et al, 1988;Hung et al, 2001;Pang et al, 2019). The first, least physiologic, but still the most widely applied in pharmacokinetics, is the well-stirred model, WSM (Pang and Rowland, 1977), alternatively called the continuously stirred tank model.…”

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confidence: 99%

In Defense of Current Concepts and Applications of Clearance in Drug Development and Therapeutics

2021

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“…Although the development of clearance concepts for the intestine has lagged behind that for the liver [51][52][53], there have been some activities trending towards the fabrication of a useful and meaningful intestine clearance model to predict the extent of removal and examine how the intestine influences the rate of liver removal according to the route of drug administration. The correct intestinal model will exert serious implications in terms of drug-drug interactions (DDIs) with inducers or inhibitors, or in terms of in vitro-in vivo extrapolation (IVIVE).…”

Section: Reason or Need For Intestinal Flow Modelsmentioning

confidence: 99%

The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions

2020

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The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (FI) and liver (FH) and the route of drug administration. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE).

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Hepatic clearance concepts and misconceptions: Why the well-stirred model is still used even though it is not physiologic reality?

Cited by 54 publications

References 65 publications

Predicting human pharmacokinetics from preclinical data: absorption

Predicting human pharmacokinetics from preclinical data: absorption

In Defense of Current Concepts and Applications of Clearance in Drug Development and Therapeutics

The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions

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