Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance
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Using lidocaine with an ER of 0.99 or higher in mice liver perfusion, its metabolite profile is well described by the well-stirred model.
“using lidocaine with an ER of 0.99 or higher, a liver perfusion experiment was conducted in mice. Its metabolite profile is well described by the well-stirred model.”
From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [45]
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The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery
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Aging Biology and Geriatric Clinical Pharmacology
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“” On the other hand, the metabolism of poorly extracted medications is described as capacity-limited because it is influenced mostly by intrinsic clearance (the metabolizing capacity) and in some cases, protein binding (Branch et al., 1973; Wilkinson and Shand, 1975; Pang and Rowland, 1977).”
BackgroundInfluentialShitara, Y., & Sugiyama, Y. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.03.003 · Cited by 574 · see citing works
Transporters as a determinant of drug clearance and tissue distribution
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EVALUATION OF DRUG-DRUG INTERACTION IN THE HEPATOBILIARY AND RENAL TRANSPORT OF DRUGS
Shitara, Y., Sato, H., & Sugiyama, Y. (2005) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.44.101802.121444 · Cited by 336 · see citing works
Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)
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“of intrinsic metabolic and biliary clearance (PSpd >> CLint,met+CLint,bile) [13]:”
Validation of a rapid equilibrium dialysis approach for the measurement of plasma protein binding.
Waters, N., Jones, R., Williams, G., & Sohal, B. (2008) · Journal of Pharmacy and Science · doi:10.1002/jps.21317 · Cited by 322 · see citing works
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Intestinal permeability and its relevance for absorption and elimination
Lennernäs, H. (2007) · Xenobiotica · doi:10.1080/00498250701704819 · Cited by 304 · see citing works
“…transporters (Clint) and is often based on the well-stirred assumption as shown in Equation (3) (Wu et al. 1995; Rostami-Hodjegan and Tucker 2007; Pang and Rowland 1977a, b, c): Eh ¼ CL Qh ðCb=CpÞ , ð3Þ where the intravenous clearance (CL) assumes no extrahepatic metabolism or renal clearance.”
MethodIn silico ADME/T modelling for rational drug design
Wang, Y., Xing, J., Xu, Y., Zhou, N., Peng, J., Xiong, Z., Liu, X., Luo, X., Luo, C., Chen, K., et al. (2015) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583515000190 · Cited by 379 · see citing works
“Compared with the well-stirred model, the parallel tube model assumes that the liver is a series of parallel tubes and that there is a declining hepatic drug concentration along the length of the tube (Pang & Rowland, 1977).”
Ito, K., & Houston, J. B. (2005) · Pharmaceutical Research · doi:10.1007/s11095-004-9015-1 · Cited by 261 · see citing works
Pharmacokinetics in the newborn.
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Prediction of Hepatic Clearance in Human From In Vitro Data for Successful Drug Development
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Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus.
Kamdem, L., Streit, F., Zanger, U., Brockmöller, J., Oellerich, M., Armstrong, V., & Wojnowski, L. (2005) · Clinical Chemistry · doi:10.1373/clinchem.2005.050047 · Cited by 224 · see citing works
“This was done according to the well-stirred (CLp1) and parallel-tube (CLp2) models (32, 33) and the respective, following equations ( 34 , 35):”
MethodMetabolic Stability for Drug Discovery and Development
Masimirembwa, C. M., Bredberg, U., & Andersson, T. B. (2003) · Clinical Pharmacokinetics · doi:10.2165/00003088-200342060-00002 · Cited by 230 · see citing works
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Pang, K. S., & Rowland, M. (1977) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01059689 · Cited by 217 · see citing works
“The two models differ in their predictions of hepatic clearance, and thus in predicting other pharmacokinetic parameters as well (1).”
BackgroundMethodInfluentialSelf-citationA microfluidic hepatic coculture platform for cell-based drug metabolism studies
Novik, E., Maguire, T. J., Chao, P., Cheng, K.-C., & Yarmush, M. L. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.11.010 · Cited by 213 · see citing works
Protein binding predictions in infants
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“CLH CLtot/RB CLR (6) CLH CLoral/RB FH Fa CLR (7) CLint,in vivo was calculated from the following equations using the well stirred (Pang and Rowland, 1977) and dispersion models (Roberts and Rowland, 1986): CLH QH 1 FH (8) Well-stirred model: FH QH/ QH fp/RB CLint (9) Disperison model: FH 4a 1…”
MethodRapid Measurement of Intracellular Unbound Drug Concentrations
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The pivotal role of hepatocytes in drug discovery
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A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations
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“Defining as intrinsic clearance CLint,z the clearance of the drug from the water in the hepatocytes within the liver element ( 6 ), it follows that”
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THE BINDING OF DRUGS TO HEPATOCYTES AND ITS RELATIONSHIP TO PHYSICOCHEMICAL PROPERTIES
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“The kinetic data from microsome or hepatocyte intrinsic clearance assays are often used for the prediction of in vivo metabolic clearance through the use of in vitro in vivo scaling using methods such as the well stirred model and the parallel tube model (Pang and Rowland, 1977).”
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“The unbound drug intrinsic clearance in vivo (CLint ub in vivo) was calculated from hepatic blood clearance using the parallel tube model (Pang and Rowland, 1977), as shown below: CLint Qh fub ln Qh CLh /Qh where CLh is hepatic blood clearance, fub is the fraction of drug unbound in blood, and Qh…”
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“A well-defined and widely used well-stirred model [10] is used to scale-up the in vitro intrinsic clearance obtained from the static culture conditions to the estimated hepatic clearance (CLH), assuming the drug is totally unbound in the serum-free culture medium:”
Rational Use of Plasma Protein and Tissue Binding Data in Drug Design
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“[I]/Ki approach The [I]/Ki approach is based upon the assumptions of a ‘well-stirred liver’ model for hepatic blood clearance (CLb,H) (Pang and Rowland 1977).”
MethodPhysiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125
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“The intrinsic clearance (GLint) values were calculated with the following assumptions; (i) the metabolism of IMM occurs only in liver, (ii) delivery of drug molecule into hepatocytes is much faster than the intracellular metabolic rate, and (iii) each physiological compartment can be described by the "well-stirred mod…”
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“paper describing the well-stirred model [25], factors that affect the hepatic clearance of a drug include: 1) blood flow to the liver, 2) intrinsic clearance, and 3) the fraction of drug bound to protein.”
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“Alternative explanations could be the altered protein binding, midazolam being highly bound to plasma proteins (98% in adults, [5]), or, less likely, reduced blood flow, because midazolam has an intermediate extraction rate [51].”
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“Moreover, a decrease in the drug’s intrinsic clearance would cause only minor changes in its total clearance but an increase in its oral bioavailability [31].”
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“6 for human IgG1) [16], Kp was set to 0.”
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“More complex models have been proposed to address the possibility that high metabolic activity causes concentration gradients to develop within the liver [30,31].”
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“8 given the fact that most developed antibodies show similar isoelectric points with native IgG1 (18).”
An integrated approach to model hepatic drug clearance
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“(10) in the text for a set of t~ values, of plasma and tissue taken from the same rat, which are listed in the next column as average + SD (n = 3-4).”
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“The inclusion of protein binding is a cornerstone in scaling, assuming that only the protein-unbound substance in plasma is accessible for metabolism (Pang and Rowland, 1977).”
BackgroundCreatine and Creatine Kinase in Health and Disease
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“where Cr~,~ is the concentration of the parent drug entering the liver (4), the steady-state output metabolite concentration in the emergent blood is”
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Dealing with the complex drug–drug interactions: Towards mechanistic models
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“The parallel-tube model assumes that the liver is composed of a series of identical and parallel tubes, along which drug concentration decreases progressively in the direction of the hepatic blood flow (Pang & Rowland 1977).”
BackgroundMethodInfluentialDrug metabolic stability in early drug discovery to develop potential lead compounds
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“The parallel tube model (Pang and Rowland 1977) considers that liver consists of a series of equal-length sinusoids or parallel tubes, through which the drug passes at a constant rate.”
BackgroundSawada, Y., Hanano, M., Sugiyama, Y., & Iga, T. (1985) · Journal of pharmacokinetics and biopharmaceutics · doi:10.1007/bf01059331 · Cited by 71 · see citing works
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Atack, J. R., Maubach, K. A., Wafford, K. A., O'Connor, D. V., Rodrigues, A. D., Evans, D. C., Tattersall, F. D., Chambers, M. S., MacLeod, A. M., Eng, W., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.157636 · Cited by 72 · see citing works
“In vivo hepatic clearances were predicted using the restrictive well stirred model (Pang and Rowland, 1977) using respective rat, dog, rhesus monkey, and human plasma protein binding values of 69, 49, 57, and 69% (data not shown).”
MethodHisaka, A., & Sugiyama, Y. (1998) · Journal of pharmacokinetics and biopharmaceutics · doi:10.1023/a:1023294632129 · Cited by 67
“To analyze local pharmacokinetics in tissues or organs, the well-stirred ( 1 ,2) and parallel tube (3,4) models are accepted as standards.”
BackgroundMethodInfluentialNishimuta, H., Houston, J., & Galetin, A. (2014) · Drug Metabolism And Disposition · doi:10.1124/dmd.114.057372 · Cited by 66 · see citing works
“6 for a subset of eight CES1 substrates (Pang and Rowland, 1977; Gertz et al., 2010) CLint;h ðml=min per kgÞ ¼ DAUC × fu;p=Rb × FG × Fa ð6Þ where D/AUC represents the hepatic blood clearance obtained from mean plasma data after correcting for renal excretion (where applicable) and the blood to…”
BackgroundRoberts, M. S., & Rowland, M. (1986) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01106707 · Cited by 95 · see citing works
“(3) for R s and assuming P >> CLint, yields the usual form (1) F = Q/(Q+fUb" CLim) (9)”
BackgroundInfluentialSelf-citationSimulating Microdosimetry in a Virtual Hepatic Lobule
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Advanced pharmacokinetic models based on organ clearance, circulatory, and fractal concepts
Pang, K. S., Weiss, M., & Macheras, P. (2007) · The AAPS Journal · doi:10.1208/aapsj0902030 · Cited by 61 · see citing works
Self-citationOchoa, J. G. D., Bucher, J., Péry, A. R. R., Comenges, J. M. Z., Niklas, J., & Mauch, K. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00204 · Cited by 60 · see citing works
“What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities.”
BackgroundInfluence of mild and moderate hepatic impairment on axitinib pharmacokinetics
Tortorici, M. A., Toh, M., Rahavendran, S. V., LaBadie, R. R., Alvey, C. W., Marbury, T. C., Fuentes, E., Green, M., Ni, G., Hee, B., et al. (2010) · Investigational New Drugs · doi:10.1007/s10637-010-9477-4 · Cited by 57 · see citing works
Strougo, A., Eißing, T., Yassen, A., Willmann, S., Danhof, M., & Freijer, J. I. (2012) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-012-9241-9 · Cited by 61 · see citing works
Lücking, U., Kosemund, D., Böhnke, N., Lienau, P., Siemeister, G., Denner, K., Bohlmann, R., Briem, H., Terebesi, I., Bömer, U., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01000 · Cited by 85 · see citing works
Empey, P. E., Miller, T. M., Philbrick, A., Melick, J. A., Kochanek, P. M., & Poloyac, S. M. (2011) · Critical Care Medicine · doi:10.1097/ccm.0b013e31823779f9 · Cited by 56 · see citing works
Use of intrinsic clearance for prediction of human hepatic clearance
Chao, P., Uss, A. S., & Cheng, K. (2010) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250903405622 · Cited by 62 · see citing works
“Here, it is clearly demonstrated that the above equation proposed by Pang and Rowland [11] with a blood/plasma free fraction correction may not work 192 Expert Opin.”
BackgroundMethodInfluentialEl-Khateeb, E., Darwich, A., Achour, B., Athwal, V., & Rostami-Hodjegan, A. (2021) · Alimentary Pharmacology and Therapeutics · doi:10.1111/apt.16489 · Cited by 57 · see citing works
Badhan, R., Penny, J., Galetin, A., & Houston, J. (2009) · Journal of Pharmacy and Science · doi:10.1002/jps.21572 · Cited by 56 · see citing works
Roberts, M., Donaldson, J., & Rowland, M. (1988) · Journal of pharmacokinetics and biopharmaceutics · doi:10.1007/bf01061862 · Cited by 55
“In the tube model, all solute molecules entering the organ at a specific time leave together whereas, in the well-stirred model, the concentration of solute is independent of position in the organ (Fig. 3). Pang and Rowland ( 4 ) have compared the steady state predictions for these two models with varying organ blood…”
BackgroundSelf-citationSolifenacin succinate for the treatment of symptoms of overactive bladder.
Maniscalco, M., Singh‐Franco, D., Wolowich, W., & Torres-Colón, R. (2006) · Clinical Therapeutics · doi:10.1016/j.clinthera.2006.09.017 · Cited by 54
Inhalation pharmacokinetics based on gas uptake studies
Filser, J., & Bolt, H. (1981) · Archives of Toxicology · doi:10.1007/bf00332394 · Cited by 54
- Authors
- Pang, K. S., & Rowland, M.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Pang, K. Sandy
- Venue
- Journal of Pharmacokinetics and Biopharmaceutics
- Published
- 1977-12
- Volume
- 5
- Issue
- 6
- Pages
- 625-653
- ISSN
- 0090-466X (ISSN-L)
- OpenAlex
- W2056455169
- Cited by
- 797
- References
- 0
- Citations by year
- 2026: 18 · 2025: 24 · 2024: 17 · 2023: 19 · 2022: 26 · 2021: 41 · 2020: 14 · 2019: 21 · 2018: 18 · 2017: 19 · 2016: 19 · 2015: 24 · 2014: 19 · 2013: 21 · 2012: 25
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Pharmacokinetics and Biopharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- hepatic clearance, well-stirred model, parallel tube model, hepatic blood flow, plasma protein binding, pharmacokinetic parameters, steady-state drug concentration
- MeSH terms
- Blood Cells, Pharmaceutical Preparations, Humans, Liver, Liver Circulation, Models, Biological
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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