The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

Berezhkovskiy, Leonid M.

doi:10.1002/jps.22324

Cited by 64Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsComputational Drug Discovery Methods

The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

Berezhkovskiy, Leonid M.·2011·Journal of Pharmaceutical Sciences

DOI 10.1002/jps.22324

Open this paper in CoChat — free account

Abstract

The estimation of hepatic clearance, Clh, using in vitro data on metabolic stability of compound, its protein binding and blood–plasma equilibrium concentration ratio is commonly performed using well-stirred, parallel tube or dispersion models. It appears that for ionizable drugs there is a difference of the steady-state concentrations in extracelluar and intracellular water (at hepatocytes), where metabolism takes place. This occurs due to the different pH of extra- and intracellular water (7.4 and 7.0, respectively). The account of this fact leads to the novel equations for Clh . These equations include the additional parameter named ionization factor, FI, which is the ratio of the unionized drug fractions in plasma and intracellular tissue water (or the ratio of the unbound drug concentrations in intracellular tissue water and plasma at equilibrium). For neutral drugs FI = 1 and the novel equations coincide with the traditional ones. It is shown that the account of this factor may yield the calculated Clh up to 6.3-fold greater than that obtained by the traditional equations for the strong diprotic basic compounds, and up to 6.3-fold smaller for the strong diprotic acidic compounds. For triprotic acids and bases the difference could be as much as 15-fold. The account of pH difference between extra- and intracellular water also results in the change of the term commonly used to describe drug metabolic elimination rate in physiologically based pharmacokinetic (PBPK) equation. This consequently may lead to a noticeable change of drug concentration-time profiles in plasma and tissues. The effect of ionization factor is especially pronounced for the low-extraction ratio drugs. The examples of significant improvement in the prediction of hepatic clearance due to the account of ionization factor are provided. A more general equation for hepatic clearance, which accounts for ionization factor and possible drug uptake and efflux, is obtained.

Integrity signals

Registry

Crossref · 10.1002/jps.22324

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

For basic compounds, the modified equation with FI could improve the prediction of CLH.
“Therefore, for basic compounds, the modified equation could improve the prediction of CLH.”
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 [71]
For acidic drugs, the conventional IVIVE equation tends to overestimate CLH.
“For acidic drugs, the conventional IVIVE equation tends to overestimate the CLH.”
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 [71]
The modified equation with FI improves the prediction of CLH for acidic compounds.
“However, this modified equation also improves the prediction of CLH for acidic compounds.”
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 [71]
Berezhkovskiy's modified equation yielded higher CLH values (up to 6.3-fold) for a basic compound (FI > 1) for strong diprotic bases, but lower CLH values (up to 6.3-fold) for an acidic compound (FI < 1) for strong diprotic acids.
“These equations yielded higher values (up to 6.3-fold) of CLH for a basic compound (FI > 1) for strong diprotic bases, but lower values (up to 6.3-fold) of CLH for an acidic compound (FI < 1) for strong diprotic acids.”
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 [71]

Prediction of Human Clearance of Twenty-Nine Drugs from Hepatic Microsomal Intrinsic Clearance Data: An Examination of In Vitro Half-Life Approach and Nonspecific Binding to Microsomes
Obach, R. S. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)14938-0 · Cited by 1,232 · see citing works
Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions
Rodgers, T., & Rowland, M. (2006) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20502 · Cited by 949 · see citing works
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
Pang, K. S., & Rowland, M. (1977) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01059688 · Cited by 797 · see citing works
Predicting the Impact of Physiological and Biochemical Processes on Oral Drug Bioavailability
Agoram, B., Woltosz, W. S., & Bolger, M. B. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00179-x · Cited by 651 · see citing works
A Review of the Microcirculation of Adipose Tissue: Anatomic, Metabolic, and Angiogenic Perspectives
Crandall, D. L., Hausman, G. J., & Kral, J. G. (1997) · Microcirculation · doi:10.3109/10739689709146786 · Cited by 508 · see citing works
Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data
Iwatsubo, T., Hirota, N., Ooie, T., Suzuki, H., Shimada, N., Chiba, K., Ishizaki, T., Green, C. E., Tyson, C. A., & Sugiyama, Y. (1997) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(96)00184-2 · Cited by 479 · see citing works
COMPARATIVE PHARMACOLOGY OF THE KETAMINE ISOMERS
White, P. F., Schüttler, J., Shafer, A., Stanski, D. R., Horai, Y., & Trevor, A. J. (1985) · British Journal of Anaesthesia · doi:10.1093/bja/57.2.197 · Cited by 416 · see citing works
A UNIFIED MODEL FOR PREDICTING HUMAN HEPATIC, METABOLIC CLEARANCE FROM IN VITRO INTRINSIC CLEARANCE DATA IN HEPATOCYTES AND MICROSOMES
Riley, R. J., McGinnity, D. F., & Austin, R. P. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.004259 · Cited by 379 · see citing works
FACTORS AFFECTING DRUG METABOLISM
Gillette, J. R. (1971) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1971.tb46890.x · Cited by 348 · see citing works
Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination
Berezhkovskiy, L. M. (2004) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20073 · Cited by 296 · see citing works
Self-citation
Metabolism and disposition of buspirone
Gammans, R. E., Mayol, R. F., & Labudde, J. A. (1986) · The American Journal of Medicine · doi:10.1016/0002-9343(86)90331-1 · Cited by 219 · see citing works
Noninvasive measurement of the pH of the endoplasmic reticulum at rest and during calcium release
Kim, J., Johannes, L., Goud, B., Antony, C., Lingwood, C. A., Daneman, R., & Grinstein, S. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.2997 · Cited by 212 · see citing works
Pharmacokinetic studies on the selectiveβ 1-receptor antagonist metoprolol in man
Regårdh, C. G., Borg, K. O., Johansson, R., Johnsson, G., & Palmer, L. (1974) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01061407 · Cited by 196 · see citing works
Pharmacokinetic–Pharmacodynamic Modelling: History and Perspectives
Csajka, C., & Verotta, D. (2006) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-005-9002-0 · Cited by 194 · see citing works
Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem
Echizen, H., & Eichelbaum, M. F. (1986) · Clinical Pharmacokinetics · doi:10.2165/00003088-198611060-00002 · Cited by 187 · see citing works
Pharmacokinetics of (+)‐, (‐)‐ and (+/‐)‐verapamil after intravenous administration.
Eichelbaum, M. F., Mikus, G., & Vogelgesang, B. (1984) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1984.tb02371.x · Cited by 178 · see citing works
Prediction of Hepatic Clearance and Availability by Cryopreserved Human Hepatocytes: An Application of Serum Incubation Method
Shibata, Y., Takahashi, H., Chiba, M., & Ishii, Y. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.8.892 · Cited by 170 · see citing works
Imipramine and desipramine disposition in the elderly.
Abernethy, D. R., Greenblatt, D. J., & Shader, R. I. (1985) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)20086-6 · Cited by 143 · see citing works
The Pharmacology of verapamil. IV. Kinetic and dynamic effects after single intravenous and oral doses
McAllister, R. G., & Kirsten, E. B. (1982) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1982.54 · Cited by 142 · see citing works
Pharmacokinetic and pharmacodynamic effects of diltiazem
Stafford‐Smith, M., Verghese, C. P., Shand, D. G., & Pritchett, E. L. C. (1983) · The American Journal of Cardiology · doi:10.1016/0002-9149(83)90314-4 · Cited by 140 · see citing works
PREDICTION OF IN VIVO DRUG DISPOSITION FROM IN VITRO DATA BASED ON PHYSIOLOGICAL PHARMACOKINETICS
Iwatsubo, T., Hirota, N., Ooie, T., SUZUKI, H., & Sugiyama, Y. (1996) · Biopharmaceutics & Drug Disposition · doi:10.1002/(sici)1099-081x(199605)17:4 · Cited by 139 · see citing works
Development of a Novel in Vitro Model to Predict Hepatic Clearance Using Fresh, Cryopreserved, and Sandwich-Cultured Hepatocytes
Lau, Y. Y., Sapidou, E., Cui, X., White, R. E., & Cheng, K.-C. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.12.1446 · Cited by 132 · see citing works
Pathway-selective sex differences in the metabolic clearance of propranolol in human subjects
Walle, T., Walle, U. K., Cowart, T. D., & Conradi, E. C. (1989) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1989.136 · Cited by 126 · see citing works
Pharmacokinetics of quinidine in humans after intravenous, intramuscular and oral administration.
Greenblatt, D. J., Pfeifer, H. J., Ochs, H. R., Franke, K., MacLaughlin, D. S., Smith, T. W., & Koch‐Weser, J. (1977) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)30967-5 · Cited by 122 · see citing works
Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration
Smith, R. B., Kroboth, P. D., VanderLugt, J. T., Phillips, J. P., & Juhl, R. P. (1984) · Psychopharmacology · doi:10.1007/bf00431449 · Cited by 115 · see citing works
Clinical Pharmacokinetics of Imipramine and Desipramine
Sallee, F. R., & Pollock, B. G. (1990) · Clinical Pharmacokinetics · doi:10.2165/00003088-199018050-00002 · Cited by 114 · see citing works
Measurement of adipose tissue blood flow and perfusion in man by uptake of 85Kr.
Lesser, G. T., & Deutsch, S. (1967) · Journal of Applied Physiology · doi:10.1152/jappl.1967.23.5.621 · Cited by 105 · see citing works
Pharmacokinetics of chlorpromazine after single and chronic dosage
Dahl, S. G., & Strandjord, R. E. (1977) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt1977214437 · Cited by 105 · see citing works
Clinical pharmacokinetics of clozapine in chronic schizophrenic patients
Cheng, Y. F., Lundberg, T., Bondesson, U., Lindstr�m, L. H., & Gabrielsson, J. (1988) · European Journal of Clinical Pharmacology · doi:10.1007/bf01046700 · Cited by 101 · see citing works
Alprazolam Metabolism in vitro: Studies of Human, Monkey, Mouse, and Rat Liver Microsomes
Moltke, L. L., Greenblatt, D. J., Harmatz, J. S., & Shader, R. I. (2008) · Pharmacology · doi:10.1159/000139107 · Cited by 100 · see citing works
Pharmacokinetics of Diphenhydramine and a Demethylated Metabolite Following Intravenous And Oral Administration
Blyden, G. T., Greenblatt, D. J., Scavone, J. M., & Shader, R. I. (1986) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1986.tb02946.x · Cited by 98 · see citing works
Kinetic determinants of hepatic clearance: Plasma protein binding and hepatic uptake
Baker, M., & Parton, T. A. H. (2007) · Xenobiotica · doi:10.1080/00498250701658296 · Cited by 95 · see citing works
A dispersion model of hepatic elimination: 2. Steady-state considerations-influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity
Roberts, M. S., & Rowland, M. (1986) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01106707 · Cited by 95 · see citing works
Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers
Ciraulo, D. A., BARNHILL, J. G., & Jaffe, J. H. (1988) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1988.66 · Cited by 91 · see citing works
First-pass metabolism of imipramine and desipramine: Impact of the sparteine oxidation phenotype
Brøsen, K., & Gram, L. F. (1988) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1988.50 · Cited by 86 · see citing works
Propafenone
Bryson, H. M., Palmer, K. J., Langtry, H. D., & Fitton, A. (1993) · Drugs · doi:10.2165/00003495-199345010-00008 · Cited by 78 · see citing works
Amitriptyline disposition in young and elderly normal men
Schulz, P., Turner-Tamiyasu, K., Smith, G. A., Giacomini, K. M., & Blaschke, T. F. (1983) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1983.46 · Cited by 74 · see citing works
Pharmacokinetics of Metoprolol in Patients with Hepatic Cirrhosis
Regårdh, C. G., Jordö, L., Ervik, M., Lundborg, P. G., Olsson, R., & Rönn, O. (1981) · Clinical Pharmacokinetics · doi:10.2165/00003088-198106050-00004 · Cited by 73 · see citing works
Stereoselective protein binding of verapamil enantiomers
Gross, A. S., Heuer, B., & Eichelbaum, M. (1988) · Biochemical Pharmacology · doi:10.1016/0006-2952(88)90330-9 · Cited by 70 · see citing works
Influence of acute viral hepatitis on disposition and plasma binding of tolbutamide
Williams, R. L., Blaschke, T. F., Meffin, P. J., Melmon, K. L., & Rowland, M. (1977) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt1977213301 · Cited by 65 · see citing works
Plasma levels of imipramine and desipramine in man after different routes of administration
Nagy, Á., & Johansson, R. (1975) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/bf00510547 · Cited by 65 · see citing works
Plasma Disappearance and Cerebral Effects of Chlorpromazine in Cirrhosis
Maxwell, J. D., Carrella, M., Parkes, J. D., Williams, R. L., Mould, G. P., & Curry, S. H. (1972) · Clinical Science · doi:10.1042/cs0430143 · Cited by 64 · see citing works
Quinidine pharmacokinetics in man: Choice of a disposition model and absolute bioavailability studies
Guentert, T. W., Holford, N. H. G., Coafes, P. E., Upton, R. A., & Riegelman, S. (1979) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01062532 · Cited by 63 · see citing works
Noncompartmentally-based pharmacokinetic modeling
Veng‐Pedersen, P. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(01)00119-3 · Cited by 61 · see citing works
Lidocaine disposition—Sex differences and effects of cimetidine
Wing, L. M. H., Miners, J. O., Birkett, D. J., Foenander, T., Lillywhite, K. J., & Wanwimolruk, S. (1984) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1984.97 · Cited by 59 · see citing works
Pharmacokinetics of Lorcainide in Man
Klotz, U. E., Müller-Seydlitz, P. M., & Heimburg, P. (1978) · Clinical Pharmacokinetics · doi:10.2165/00003088-197803050-00006 · Cited by 48 · see citing works
The distribution of quinidine in human blood.
Hughes, I., Ilett, K., & Jellett, L. B. (1975) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.1975.tb00570.x · Cited by 41 · see citing works
Timolol and propranolol: Bioavailability, plasma concentrations, and beta blockade
Wilson, T. W., Firor, W. B., Johnson, G. E., Holmes, G. I., TSIANCO, M. C., Huber, P. B., & Davies, R. O. (1982) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1982.223 · Cited by 41 · see citing works
On the influence of protein binding on pharmacological activity of drugs
Berezhkovskiy, L. M. (2009) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21958 · Cited by 40 · see citing works
Self-citation
Pharmacokinetics of quinidine and three of its metabolites in man
Rakhit, A. K., Holford, N. H. G., Guentert, T. W., Maloney, K., & Riegelman, S. (1984) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01063608 · Cited by 32 · see citing works
Binding of two adrenergic beta-receptor antagonists, alprenolol and H 93-26, to human serum proteins.
Ka, J., Appelgren, C., Borg, K. O., & Elofsson, R. (1974) · PubMed · Cited by 31 · see citing works
Intracellular pH of hepatocytes in primary monolayer culture
Pollock, A. S. (1984) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.1984.246.5.f738 · Cited by 29 · see citing works
A Valid Equation for the Well-Stirred Perfusion Limited Physiologically Based Pharmacokinetic Model that Consistently Accounts for the Blood–Tissue Drug Distribution in the Organ and the Corresponding Valid Equation for the Steady State Volume of Distribution
Berezhkovskiy, L. M. (2009) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21798 · Cited by 28 · see citing works
Self-citation
Naloxone protein binding in adult and foetal plasma
Asali, L. A., & Brown, K. F. (1984) · European Journal of Clinical Pharmacology · doi:10.1007/bf00549595 · Cited by 23 · see citing works
On the prediction of hepatic clearance using the diluted plasma in metabolic stability assay.
Berezhkovskiy, L. M., Khojasteh, S. C., Halladay, J. S., & Hop, C. (2009) · Journal of Pharmacy and Science · doi:10.1002/jps.21582 · Cited by 20 · see citing works
Self-citation
Determination of Mean Residence Time of Drug in Plasma and the Influence of the Initial Drug Elimination and Distribution on the Calculation of Pharmacokinetic Parameters
Berezhkovskiy, L. M. (2008) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.21440 · Cited by 18 · see citing works
Self-citation
Lack of effect of cimetidine on the metabolism of quinidine: effect on renal clearance.
Hardy, B. G., & Schentag, J. J. (1988) · PubMed · Cited by 18 · see citing works
Excretion of tolbutamide metabolites in young and old subjects
Miller, A. K., Adir, J., & Vestal, R. E. (1990) · European Journal of Clinical Pharmacology · doi:10.1007/bf02336696 · Cited by 15 · see citing works
The Distribution of Chlorpromazine between Plasma and Erythrocytes
Lund, A. (1980) · Acta Pharmacologica et Toxicologica · doi:10.1111/j.1600-0773.1980.tb03658.x · Cited by 11 · see citing works
On the determination of the time delay in reaching the steady state drug concentration in the organ compared to plasma
Berezhkovskiy, L. M. (2007) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.20986 · Cited by 10 · see citing works
Self-citation
Microionization constants: novel approach for the determination of the zwitterionic equilibrium of hydroxyphenylalkylamines by photometric titration
Peinhardt, G. P., & Wiese, M. (2001) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(00)00673-6 · Cited by 10 · see citing works
Comparison of the effects of desipramine on noradrenaline- and methoxamine-evoked venoconstriction in man.
Abdelmawla, A. H., Langley, R. W., Szabadi, E., & Bradshaw, C. M. (1995) · PubMed Central · Cited by 8 · see citing works
The Effects Of Hemodilution, pH, and Protamine on Lidocaine Plasma Protein Binding and Red Blood-Cell Uptake in Vitro
Remmel, R. P., Copa, A. K., & Angaran, D. M. (1991) · Pharmaceutical Research · doi:10.1023/a:1015807129129 · Cited by 7 · see citing works
Pharmacokinetic Implications of Lorcainide Therapy in Patients With Normal and Depressed Cardiac Function
Somani, P., Fraker, T. D., & Temesy‐Armos, P. N. (1987) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1987.tb02172.x · Cited by 5 · see citing works

Flagged first, then by citations

Sorted by citations

Physiologically based pharmacokinetic modeling in drug discovery and development: A pharmaceutical industry perspective
Jones, H., Chen, Y., Gibson, C., Heimbach, T., Parrott, N., Peters, S., Snoeys, J., Upreti, V., Zheng, M., & Hall, S. (2015) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.37 · Cited by 488 · see citing works
Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells)
Kazmi, F., Hensley, T. N., Pope, C. A., Funk, R. S., Loewen, G. J., Buckley, D. B., & Parkinson, A. (2013) · Drug Metabolism and Disposition · doi:10.1124/dmd.112.050054 · Cited by 259 · see citing works
Crosstalk of physiological pH and chemical pKa under the umbrella of physiologically based pharmacokinetic modeling of drug absorption, distribution, metabolism, excretion, and toxicity
Gaohua, L., Miao, X., & Liu, D. (2021) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2021.1951223 · Cited by 204 · see citing works
Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac
Chan, T. S., Yu, H., Moore, A., Khetani, S. R., & Tweedie, D. (2013) · Drug Metabolism and Disposition · doi:10.1124/dmd.113.053397 · Cited by 150 · see citing works
Estimating human ADME properties, pharmacokinetic parameters and likely clinical dose in drug discovery
Lucas, A. J., Sproston, J. L., Barton, P., & Riley, R. J. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1660642 · Cited by 144 · see citing works
Special Section on Pharmacokinetic and Drug Metabolism Properties of Novel Therapeutic Modalities–Minireview
Zhang, D., Hop, C. E. C. A., Patilea-Vrana, G., Gampa, G., Seneviratne, H. K., Unadkat, J. D., Kenny, J. R., Nagapudi, K., Di, L., Zhou, L., et al. (2019) · Drug Metabolism and Disposition · doi:10.1124/dmd.119.086744 · Cited by 121 · see citing works
In Vitro–In Vivo Extrapolation of Clearance: Modeling Hepatic Metabolic Clearance of Highly Bound Drugs and Comparative Assessment with Existing Calculation Methods
Poulin, P., Kenny, J. R., Hop, C. E. C. A., & Haddad, S. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22792 · Cited by 109 · see citing works
An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation
Bowman, C. M., & Benet, L. Z. (2018) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2018.08.008 · Cited by 95 · see citing works
When is Protein Binding Important?*
Heuberger, J. A. A. C., Schmidt, S., & Derendorf, H. (2013) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23559 · Cited by 83 · see citing works
Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling
Choi, G.-W., Lee, Y.-B., & Cho, H.-Y. (2019) · Pharmaceutics · doi:10.3390/pharmaceutics11040168 · Cited by 76 · see citing works
“Berezhkovskiy [71] has developed a modified equation to predict CLH based on differences in intra- and extra-cellular pH of the unbound drug fraction using FI as presented in Equations (57) to (60).”
BackgroundMethod
VIVD: Virtual in vitro distribution model for the mechanistic prediction of intracellular concentrations of chemicals in in vitro toxicity assays
Fisher, C. P., Siméon, S., Jamei, M., Gardner, I., & Bois, Y. F. (2018) · Toxicology in Vitro · doi:10.1016/j.tiv.2018.12.017 · Cited by 74 · see citing works
Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization
Sodhi, J., & Benet, L. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01930 · Cited by 55 · see citing works
Comparative Assessment of In Vitro–In Vivo Extrapolation Methods used for Predicting Hepatic Metabolic Clearance of Drugs
Poulin, P., Hop, C. E. C. A., Ho, Q., Halladay, J. S., Haddad, S., & Kenny, J. R. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23288 · Cited by 64 · see citing works
Evaluation of Hepatic Clearance Prediction Using In Vitro Data: Emphasis on Fraction Unbound in Plasma and Drug Ionisation Using a Database of 107 Drugs
Hallifax, D., & Houston, J. B. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23202 · Cited by 60 · see citing works
Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data
Yadav, J., Hassani, M. E., Sodhi, J. K., Lauschke, V. M., Hartman, J. H., & Russell, L. E. (2021) · Drug Metabolism Reviews · doi:10.1080/03602532.2021.1922435 · Cited by 57 · see citing works
A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein‐bound drugs and the impact of errors in plasma protein binding
Ye, M., Nagar, S., & Korzekwa, K. (2015) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1996 · Cited by 54 · see citing works
Evaluation of the Disconnect between Hepatocyte and Microsome Intrinsic Clearance and In Vitro In Vivo Extrapolation Performance
Williamson, B., Harlfinger, S., & McGinnity, D. F. (2020) · Drug Metabolism and Disposition · doi:10.1124/dmd.120.000131 · Cited by 48 · see citing works
Quantitation of Lysosomal Trapping of Basic Lipophilic Compounds Using In Vitro Assays and In Silico Predictions Based on the Determination of the Full pH Profile of the Endo-/Lysosomal System in Rat Hepatocytes
Schmitt, M. V., Lienau, P., Fricker, G., & Reichel, A. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.118.084541 · Cited by 46 · see citing works
Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac
Chan, T. S., Yu, H., Moore, A., Khetani, S. R., & Tweedie, D. (2018) · Drug Metabolism and Disposition · doi:10.1124/dmd.113.053397fullarticlecorrection · Cited by 41 · see citing works
Application of Empirical Scalars To Enable Early Prediction of Human Hepatic Clearance Using In Vitro-In Vivo Extrapolation in Drug Discovery: An Evaluation of 173 Drugs
Jones, R. S., Leung, C., Chang, J. H., Brown, S., Liu, N., Yan, Z., Kenny, J. R., & Broccatelli, F. (2022) · Drug Metabolism and Disposition · doi:10.1124/dmd.121.000784 · Cited by 40 · see citing works
Analysis of the impact of controlled release formulations on oral drug absorption, gut wall metabolism and relative bioavailability of CYP3A substrates using a physiologically-based pharmacokinetic model
Olivares‐Morales, A., Kamiyama, Y., Darwich, A. S., Aarons, L. J., & Rostami‐Hodjegan, A. (2014) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2014.10.018 · Cited by 40 · see citing works
Design and Measurement of Drug Tissue Concentration Asymmetry and Tissue Exposure-Effect (Tissue PK-PD) Evaluation
Zang, R., Barth, A., Wong, H., Mařı́k, J., Shen, J., Lade, J. M., Grove, K. J., Durk, M. R., Parrott, N. J., Rudewicz, P. J., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00502 · Cited by 37 · see citing works
The potential protein-mediated hepatic uptake: discussion on the molecular interactions between albumin and the hepatocyte cell surface and their implications for the in vitro-to-in vivo extrapolations of hepatic clearance of drugs
Bteich, M., Poulin, P., & Haddad, S. (2019) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2019.1640679 · Cited by 37 · see citing works
Drug Distribution to Human Tissues: Prediction and Examination of the Basic Assumption in In Vivo Pharmacokinetics-Pharmacodynamics (PK/PD) Research
Poulin, P. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24427 · Cited by 37 · see citing works
Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding
Da-silva, F., Boulenc, X., Vermet, H., Compigne, P., Gerbal‐Chaloin, S., Daujat‐Chavanieu, M., Klieber, S., & Poulin, P. (2018) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2018.03.001 · Cited by 36 · see citing works
Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362
Lowe, M. A., Cardenas, A., Valentin, J., Zhu, Z., Abendroth, J. A., Castro, J. L., Class, R., Delaunois, A. G., Fleurance, R., Gerets, H. H. J., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01336 · Cited by 35 · see citing works
In Vitro- in Vivo Extrapolation of Hepatic Metabolism for Different Scenarios - a Toolbox.
Krause, S., & Goss, K. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00187 · Cited by 29 · see citing works
Plasma protein-mediated uptake and contradictions to the free drug hypothesis: a critical review
Schulz, J., Stresser, D. M., & Kalvass, J. C. (2023) · Drug Metabolism Reviews · doi:10.1080/03602532.2023.2195133 · Cited by 31 · see citing works
Extrapolation of the Hepatic Clearance of Drugs in the Absence of Albumin In Vitro to That in the Presence of Albumin In Vivo : Comparative Assessement of 2 Extrapolation Models Based on the Albumin-Mediated Hepatic Uptake Theory and Limitations and Mechanistic Insights
Poulin, P., & Haddad, S. (2018) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2018.03.012 · Cited by 29 · see citing works
The Impact of the Hepatocyte-to-Plasma pH Gradient on the Prediction of Hepatic Clearance and Drug-Drug Interactions for CYP2D6 Substrates
Rougée, L. R. A., Mohutsky, M. A., Bedwell, D. W., Ruterbories, K. J., & Hall, S. D. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.071761 · Cited by 24 · see citing works
A Paradigm Shift in Pharmacokinetic–Pharmacodynamic (PKPD) Modeling: Rule of Thumb for Estimating Free Drug Level in Tissue Compared with Plasma to Guide Drug Design
Poulin, P. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24468 · Cited by 23 · see citing works
From Genotype to Phenotype: Cytochrome P450 2D6-Mediated Drug Clearance in Humans
Gao, J., Tian, X., Zhou, J., Cui, M., Zhang, H., Gao, N., Wen, Q., & Qiao, H. (2017) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.6b00920 · Cited by 22 · see citing works
Verapamil hepatic clearance in four preclinical rat models: towards activity‐based scaling
Nicolaï, J., de Bruyn, T., Veldhoven, P. V., Keemink, J., Augustijns, P., & Annaert, P. (2015) · Biopharmaceutics & drug disposition · doi:10.1002/bdd.1959 · Cited by 15 · see citing works
The Impact of the Hepatocyte-to-Plasma pH Gradient on the Prediction of Hepatic Clearance and Drug-Drug Interactions for CYP2C9 and CYP3A4 Substrates
Rougée, L. R. A., Mohutsky, M. A., Bedwell, D. W., Ruterbories, K. J., & Hall, S. D. (2017) · Drug Metabolism and Disposition · doi:10.1124/dmd.117.076331 · Cited by 17 · see citing works
In SilicoModeling for the Prediction of Dose and Pathway-Related Adverse Effects in Humans FromIn VitroRepeated-Dose Studies
Klein, S. G., Maggioni, S., Bucher, J., Mueller, D., Niklas, J., Shevchenko, V., Mauch, K., Heinzle, E., & Noor, F. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv218 · Cited by 17 · see citing works
Prediction of Drug Terminal Half-Life and Terminal Volume of Distribution After Intravenous Dosing Based on Drug Clearance, Steady-State Volume of Distribution, and Physiological Parameters of the Body
Berezhkovskiy, L. M. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23396 · Cited by 16 · see citing works
Self-citation
A New Guidance for the Prediction of Hepatic Clearance in the Early Drug Discovery and Development from the in Vitro-to-in Vivo Extrapolation Method and an Approach for Exploring Whether an Albumin-Mediated Hepatic Uptake Phenomenon Could be Present Under in Vivo Conditions
Poulin, P., & Haddad, S. (2021) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2021.04.002 · Cited by 14 · see citing works
An Algorithm for Evaluating Potential Tissue Drug Distribution in Toxicology Studies from Readily Available Pharmacokinetic Parameters
Poulin, P., Dambach, D. M., Hartley, D. H., Ford, K. A., Theil, F., Harstad, E. B., Halladay, J. S., Choo, E. F., Boggs, J. W., Liederer, B. M., et al. (2013) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23670 · Cited by 13 · see citing works
Probe ADME and Test Hypotheses: a PATH beyond clearance in vitro–in vivo correlations in early drug discovery
Bell, L., & Wang, J. (2012) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2012.695346 · Cited by 13 · see citing works
Pharmacokinetic variations in cancer patients with liver dysfunction: applications and challenges of pharmacometabolomics
Dahab, A. A., El-Hag, D., Moutamed, G., Dahab, S. A., Abuknesha, R. A., & Smith, N. W. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-016-3028-4 · Cited by 12 · see citing works
Determination of Hepatic Clearance with the Account of Drug–Protein Binding Kinetics
Berezhkovskiy, L. M. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23235 · Cited by 11 · see citing works
Self-citation
The influence of hepatic transport on the distribution volumes and mean residence time of drug in the body and the accuracy of estimating these parameters by the traditional pharmacokinetic calculations
Berezhkovskiy, L. M. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22696 · Cited by 10 · see citing works
Self-citation
Successful Prediction of Human Pharmacokinetics by Improving Calculation Processes of Physiologically Based Pharmacokinetic Approach.
Mayumi, K., Ohnishi, S., & Hasegawa, H. (2019) · Journal of Pharmacy and Science · doi:10.1016/j.xphs.2019.03.002 · Cited by 10 · see citing works
Consistency of the Novel Equations for Determination of Hepatic Clearance and Drug Time Course in Liver that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water
Berezhkovskiy, L. M., Liu, N., & Halladay, J. S. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23000 · Cited by 10 · see citing works
Self-citation
On the Accuracy of Determination of Unbound Drug Fraction in Tissue using Diluted Tissue Homogenate
Berezhkovskiy, L. M. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23073 · Cited by 8 · see citing works
Self-citation
On the maintenance of hepatocyte intracellular pH 7.0 in the in-vitro metabolic stability assay
Berezhkovskiy, L. M., Wong, S., & Halladay, J. S. (2013) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-013-9339-8 · Cited by 7 · see citing works
Self-citation
Investigation of the prerequisites for the optimization of specific plasma protein binding as a strategy for the reduction of first-pass hepatic metabolism
Svennebring, A. M. (2014) · Xenobiotica · doi:10.3109/00498254.2014.978413 · Cited by 6 · see citing works
On the accuracy of calculation of the mean residence time of drug in the body and its volumes of distribution based on the assumption of central elimination
Berezhkovskiy, L. M. (2015) · Xenobiotica · doi:10.3109/00498254.2015.1089366 · Cited by 5 · see citing works
Self-citation
Conceptual underestimation of the total body clearance by the sum of clearances of individual organs in physiologically based pharmacokinetics
Berezhkovskiy, L. M. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23327 · Cited by 5 · see citing works
Self-citation
A Novel Experimental and Theoretical Method for Estimating Albumin-Mediated Hepatic Uptake Based on the Albumin Binding Fraction in Plasma and Human PK Prediction Using a Physiologically-Based Pharmacokinetic Approach
Egashira, Y., Shimada, T., & Mayumi, K. (2021) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2021.01.015 · Cited by 4 · see citing works
Exploration of PBPK Model—Calculation of Drug Time Course in Tissue Using IV Bolus Drug Plasma Concentration-Time Profile and the Physiological Parameters of the Organ
Berezhkovskiy, L. M. (2016) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2016.04.019 · Cited by 2 · see citing works
Self-citation
SYSTEM-DEPENDENT METABOLISM OF DRUGS BY CYTOCHROME P450: THE MECHANISTIC BASIS FOR WHY HUMAN LIVER MICROSOMES ARE SUPERIOR TO HUMAN HEPATOCYTES AT METABOLIZING MIDAZOLAM BUT INFERIOR AT METABOLIZING DESLORATADINE
Kazmi, F. (2015) · KU ScholarWorks (University of Kansas) · Cited by 2 · see citing works
Special Section on Prediction of Human Pharmacokinetic Parameters from In Vitro Systems Meeting the Challenge of Predicting Hepatic Clearance of Compounds Slowly Metabolized by Cytochrome P450 Using a Novel Hepatocyte Model, HepatoPac
Chan, T. S., Yu, H., Moore, A., Khetani, S. R., & Tweedie, D. (2013) · Cited by 1 · see citing works
Models for Nonspecific Binding and Partitioning
Korzekwa, K. (2015) · Royal Society of Chemistry eBooks · doi:10.1039/9781782622376-00053 · Cited by 1 · see citing works
Path (Probe ADME and Test Hypotheses): A Useful Approach Enabling Hypothesis‐Driven ADME Optimization
Bell, L., Skolnik, S. M., & Bednarczyk, D. (2014) · doi:10.1002/9781118783344.ch4
Consequences of a lack of adult intravenous data on the prediction accuracy of pediatric physiologically based pharmacokinetic (PBPK) modeling
Chandani, R. (2015) · UWSpace (University of Waterloo)
In vitro-in vivo extrapolation of human hepatic and renal clearance
Alluri, R. V., & Varma, M. V. S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-820018-6.00022-3
Implications of In Vitro System Conditions for CYP2C9 and CYP3A4: Impact of pH on Clearance and Enzyme Inhibition
Rougée, L. R. A., Mohutsky, M. A., Bedwell, D. W., Ruterbories, K. J., & Hall, S. D. (2016) · The FASEB Journal · doi:10.1096/fasebj.30.1_supplement.934.8
Mechanistic Basis of Clearance
Chen, E. P. (2025) · doi:10.1002/9781119650263.ch05
Impact of POR and cytochrome b5 variability on the genotype-phenotype discordance of CYP2A6 and CYP2D6: A quantitative analysis in Chinese human livers
Yan, F., Wang, J., Liu, D., Li, J., Tian, X., Gao, N., Zhang, H., Wen, Q., & Qiao, H. (2026) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2026.100264
Evaluation of the disconnect between hepatocyte and microsomal intrinsic clearance at intracellular and extracellular pH.
Maurer, C. K., Fang, Z., Harlfinger, S., & Petersson, C. (2026) · Drug Metabolism And Disposition · doi:10.1016/j.dmd.2026.100288
Amélioration de la prédiction de la clairance métabolique via l’utilisation de modèles hépatiques innovants
Silva, F. D. (2018) · doi:10.70675/a1ef7558z4d24z4e76zb646zb00718717192
Modélisation pharmacocinétique et pharmacodynamique de la toxicité développementale de l'embryon de poisson zèbre.
Siméon, S. (2020) · theses.fr (ABES) · doi:10.70675/e21b1231za4b9z43cfzb273zfc8e1d49b533
BindingDB Entry 50016003: Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of
BindingDB (2023) · UC San Diego · doi:10.7270/q2988c16

Consistency of the Novel Equations for Determination of Hepatic Clearance and Drug Time Course in Liver that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water
Berezhkovskiy, L. M., Liu, N., & Halladay, J. S. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23000 · Cited by 10 · see citing works
Self-citation
On the maintenance of hepatocyte intracellular pH 7.0 in the in-vitro metabolic stability assay
Berezhkovskiy, L. M., Wong, S., & Halladay, J. S. (2013) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-013-9339-8 · Cited by 7 · see citing works
Self-citation
Evaluation of the disconnect between hepatocyte and microsomal intrinsic clearance at intracellular and extracellular pH.
Maurer, C. K., Fang, Z., Harlfinger, S., & Petersson, C. (2026) · Drug Metabolism And Disposition · doi:10.1016/j.dmd.2026.100288
Relationships between the Hepatic Intrinsic Clearance or Blood Cell-Plasma Partition Coefficient in the Rabbit and the Lipophilicity of Basic Drugs
Ishizaki, J., Yokogawa, K., Nakashima, E., & Ichimura, F. (1997) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.1997.tb06109.x · Cited by 22 · see citing works
Assessing Liver-to-Plasma Partition Coefficients and In Silico Calculation Methods: When Does the Hepatic Model Matter in PBPK?
Li, X., & Jusko, W. J. (2022) · Drug Metabolism and Disposition · doi:10.1124/dmd.122.000994 · Cited by 22 · see citing works

Authors: Berezhkovskiy, L. M.
Affiliations: Genentech (US)
Corresponding author: Berezhkovskiy, Leonid M.
Venue: Journal of Pharmaceutical Sciences
Publisher: Elsevier BV
Published: 2011-03
Volume: 100
Issue: 3
Pages: 1167-1183
ISSN: 0022-3549 (ISSN-L)
DOI: 10.1002/jps.22324
OpenAlex: W2047951338
Cited by: 63
References: 64
Citations by year: 2026: 2 · 2025: 1 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 8 · 2017: 2 · 2016: 4 · 2015: 10 · 2014: 3 · 2013: 6 · 2012: 7
FWCI: 5.16
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Pharmaceutical Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords: hepatic clearance, drug ionization, intracellular pH, physiologically based pharmacokinetic modeling, ionizable drugs, extraction ratio, drug metabolism, unbound drug concentration
MeSH terms: Algorithms, Pharmaceutical Preparations, Humans, Hydrogen-Ion Concentration, Intracellular Fluid, Liver, Metabolic Clearance Rate, Models, Biological, Pharmacokinetics, Protein Binding, Tissue Distribution, Hepatocytes, Extracellular Fluid

About these checks

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks