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General approach for the calculation of tissue to plasma partition coefficients
Abstract
A new mechanistic, universal model for the calculation of steady state tissue:plasma partition coefficients (Kt:p) of organic chemicals in mammalian species was developed. The approach allows the estimation of Kt:p-values based on the composition of the tissues in terms of water, neutral lipids, neutral and acidic phospholipids and proteins using the lipophilicity, the binding to phospholipid membranes, the pKa and the unbound fraction in blood plasma as compound specific parameters. Taking explicitly into account the sign and fraction of the charge of the compounds at the physiological pH the method is universally applicable to neutral, acidic, basic or multiply charged substances and has thus a significantly extended applicability compared to previously published approaches. The model was applied to 59 chemically diverse drug compounds for which tissue:plasma partition coefficients are reported in the literature. In total 474 experimentally observed Kt:p values for 12 tissues and the red blood cells were available and could be compared to model results. For 73% of the calculated values a deviation less than 3-fold from the respective observed value was found, proving the validity of the approach.
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“In addition to the mechanistic models available in Simcyp for estimation of K p values, the PK‐Sim standard 45 and Schmitt 46 models can be applied in PK‐Sim.”
From Does the choice of applied physiologically‐based pharmacokinetics platform matter? A case study on simvastatin disposition and drug–drug interaction (2022) · cites this paper as [46]
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“The computational chemistry approaches extend previous efforts in the pharmaceutical industry to estimate tissue partition coefficients using physico-chemical properties (Pearce et al. , 2017a; Schmitt, 2008) to capture a broader range of chemical space (Wambaugh et al. , 2018).”
MethodPBPK models for the prediction of in vivo performance of oral dosage forms
Kostewicz, E. S., Aarons, L. J., Bergstrand, M., Bolger, M. B., Galetin, A., Hatley, O. J. D., Jamei, M., Lloyd, R. S., Pepin, X. J. H., Rostami‐Hodjegan, A., et al. (2013) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2013.09.008 · Cited by 322
“The fractions of lipid, protein, and water in each organ and sub-compartment are embedded in the software, enabling the calculation of tissue–plasma-partition coefficients using five different approaches (PK-Sim standard (PK-Sim , 2012), Rodgers and Rowland (Rodgers et al., 2005a,b; Rodgers and Rowland, 2006, 2007), S…”
MethodApplications of Polyparameter Linear Free Energy Relationships in Environmental Chemistry
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httk : R Package for High-Throughput Toxicokinetics
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“Vdist is used as the volume of the compartment and is calculated by summing the plasma volume and the products of each tissue to unbound plasma partition coefficient, its corresponding volume, and fub (Schmitt 2008b).”
InfluentialCapacities of Membrane Lipids to Accumulate Neutral Organic Chemicals
Endo, S., Escher, B. I., & Goss, K. (2011) · Environmental Science & Technology · doi:10.1021/es200855w · Cited by 290
Groothuis, F. A., Heringa, M. B., Nicol, B., Hermens, J. L. M., Blaauboer, B. J., & Kramer, N. I. (2013) · Toxicology · doi:10.1016/j.tox.2013.08.012 · Cited by 284
“The partitioning of positively charged chemicals to membranes is similar or even enhanced compared to that of neutral compounds with equal hydrophobicity towards cell membranes or microsomes (Austin et al., 1995, 2002; Escher and Schwarzenbach, 1996; Kramer et al., 1998; Schmitt, 2008).”
Shi, Y., Vestergren, R., Zhou, Z., Song, X., Xu, L., Liang, Y., & Cai, Y. (2015) · Environmental Science & Technology · doi:10.1021/acs.est.5b04299 · Cited by 258
In vitro to in vivo extrapolation for high throughput prioritization and decision making
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Quantitativein vitrotoin vivoextrapolation of cell-based toxicity assay results
Yoon, M., Campbell, J. L., Andersen, M. E., & M.A., H. J. C. I. (2012) · Critical Reviews in Toxicology · doi:10.3109/10408444.2012.692115 · Cited by 217
“E-mail: HClewell@thehamner.org (Received 17 October 2011; revised 25 April 2012; accepted 06 May 2012) 1040-8444 1547-6898 © 2012 Informa Healthcare USA, Inc. 10.3109/10408444.2012.692115 Critical Reviews in Toxicology”
BackgroundInfluentialEissing, T. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00004 · Cited by 204
“…by Willmann et al. (2003a), Rodgers et al. (Rodgers et al., 2005a,b; Rodgers and Rowland, 2006, 2007), Poulin et al. (Poulin et al., 2001; Poulin and Theil, 2002a,b), Berezhkovskiy (2004), Schmitt (2008), as well as a newly developed proprietary distribution model dedicated to biologicals.”
BackgroundMachine learning and artificial intelligence in physiologically based pharmacokinetic modeling
Chou, W., & Lin, Z. (2022) · Toxicological Sciences · doi:10.1093/toxsci/kfac101 · Cited by 208
Armitage, J. M., Arnot, J. A., Wania, F., & Mackay, D. (2012) · Environmental Toxicology and Chemistry · doi:10.1002/etc.2020 · Cited by 187
“ods for estimating the tissue–plasma partitioning of IOCs have also been described in the literature [14,15].”
BackgroundMethodKhalil, F., & Läer, S. (2011) · BioMed Research International · doi:10.1155/2011/907461 · Cited by 155
“A great deal of specialized PBPK modeling software includes such algorithms—for instance, those developed by Poulin and Theil, Rodgers and Rowland, or Schmitt [21–23] to calculate tissue:plasma partition coefficients.”
MethodWhole body physiologically-based pharmacokinetic models: their use in clinical drug development
Edginton, A. N., Theil, F., Schmitt, W., & Willmann, S. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.9.1143 · Cited by 159
“It was a major breakthrough when biophysical models became available that enabled a valid prediction of organ: plasma partition coefficients based on simple physicochemical properties such as lipophilicity and acid/base properties [14-19] .”
BackgroundSelf-citationPBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment
Bessems, J. G. M., Loizou, G. D., Krishnan, K., M.A., H. J. C. I., Bernasconi, C., Bois, F. Y., Coecke, S., Collnot, E.-M., Diembeck, W., Farcal, L. R., et al. (2013) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2013.11.008 · Cited by 161
Armitage, J. M., Erickson, R. J., Luckenbach, T., Ng, C. A., Prosser, R. S., Arnot, J. A., Schirmer, K., & Nichols, J. W. (2016) · Environmental Toxicology and Chemistry · doi:10.1002/etc.3680 · Cited by 152
“For example, tissue/plasma distribution ratios predicted by Schmitt [96] using an equilibrium partitioning approach differed from measured values by a factor of approximately 1.5 to 5.0, depending on the tissue.”
BackgroundMethodInfluentialAn Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library
Sipes, N. S., Wambaugh, J., Pearce, R. G., Auerbach, S., Wetmore, B., Hsieh, J.-H., Shapiro, A. J., Svoboda, D. L., DeVito, M., & Ferguson, S. (2017) · Environmental Science and Technology · doi:10.1021/acs.est.7b00650 · Cited by 140
Toxicokinetic Triage for Environmental Chemicals
Wambaugh, J. F., Wetmore, B. A., Pearce, R., Strope, C. L., Goldsmith, R., Sluka, J. P., Sedykh, A., Tropsha, A., Bosgra, S., Shah, I., et al. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfv118 · Cited by 145
“Chemical-specific tissue to free fraction in plasma partition coefficients were predicted using Schmitt’s method (2008a). Tissue-specificity was based upon the cellular fraction of total volume; water, lipid and protein fraction of cellular volume; and distribution of types of lipid (Schmitt, 2008b).”
MethodEvaluating In Vitro-In Vivo Extrapolation of Toxicokinetics
Wambaugh, J. F., Hughes, M. F., Ring, C., MacMillan, D. K., Ford, J., Fennell, T. R., Black, S. R., Snyder, R. W., Sipes, N. S., Wetmore, B. A., et al. (2018) · Toxicological Sciences · doi:10.1093/toxsci/kfy020 · Cited by 149
“Steady-state Vd was predicted as in Poulin and Theil (2009) using a modified version of Schmitt’s method (Schmitt, 2008), wherein the total volume of distribution was calculated as the sum of tissue-specific partition coefficient predictions weighted by the species appropriate tissue volumes…”
MethodKarrer, C., Roiss, T., Goetz, N. V., Skledar, D. G., Mašič, L. P., & Hungerbühler, K. (2018) · Environmental Health Perspectives · doi:10.1289/ehp2739 · Cited by 136
“Tissue/serum partition coefficients for BPS, BPF, and BPAF calculated with the quantitative structure-activity relationships by DeJongh et al. (1997) and Schmitt (2008), partially used as boundaries in the uncertainty distributions.”
MethodInfluentialCharacterization and application of physiologically based pharmacokinetic models in risk assessment
Buist, H. E. (2010) · TNO Repository · Cited by 137
Peyret, T., Poulin, P., & Krishnan, K. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.09.010 · Cited by 136
“…non-ionic form in the water phase as per Poulin and Krishnan (1995a), Poulin and Theil (2000), Rodgers et al. (2005), Rodgers and Rowland (2006) and Schmitt (2008), as follows: Cm = Cnwd 1 + Imð Þd Fwm + Cnwd Powd Fnlm + Cnwd Imd Paplwd Faplm + Cnwd 1 + Imð Þd Pprwd Fprm ð2Þ where Cm:…”
BackgroundMethodInfluentialThelen, K., Coboeken, K., Willmann, S., Burghaus, R., Dressman, J. B., & Lippert, J. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22726 · Cited by 139
Endo, S., Brown, T. N., & Goss, K. (2013) · Environmental Science & Technology · doi:10.1021/es401772m · Cited by 134
A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim
Niederalt, C., Kuepfer, L., Solodenko, J., Eißing, T., Siegmund, H., Block, M. S., Willmann, S., & Lippert, J. (2017) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-017-9559-4 · Cited by 121
“The generic model in PK-Sim is thus able to describe the generally relevant processes of passive distribution and clearance of therapeutic antibodies.”
BackgroundMethodInfluentialThiel, C., Schneckener, S., Krauß, M., Ghallab, A., Hofmann, U., Kanacher, T., Zellmer, S., Gebhardt, R., Hengstler, J. G., & Kuepfer, L. (2014) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24214 · Cited by 119
Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability
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“KRBC2p was predicted from physico-chemical properties using Schmitt's method (Schmitt, 2008).”
MethodDose Selection Based on Physiologically Based Pharmacokinetic (PBPK) Approaches
Jones, H. M., Mayawala, K., & Poulin, P. (2012) · The AAPS Journal · doi:10.1208/s12248-012-9446-2 · Cited by 111
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High-throughput PBTK models for in vitro to in vivo extrapolation
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“mass and volume of the body unaccounted for by the tissues included in Schmitt [125], which is determined with the averages of the fractional volumes and pH of these tissues, excluding red blood cells [40].”
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“5 and 6 for the Poulin and Theil and Schmitt model, respectively.”
MethodInfluentialDomínguez-Romero, E., & Scheringer, M. (2019) · Drug Metabolism Reviews · doi:10.1080/03602532.2019.1620762 · Cited by 86
“Other algorithms exist, some of which include the processes of binding and ionization (Poulin and Theil 2000; Schmitt 2008; Peyret et al. 2010).”
BackgroundYang, X., Doerge, D. R., Teeguarden, J., & Fisher, J. W. (2015) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2015.10.016 · Cited by 86
Armitage, J. M., Arnot, J. A., & Wania, F. (2012) · Environmental Science & Technology · doi:10.1021/es304430r · Cited by 82
Modeling Kinetics of Subcellular Disposition of Chemicals
Baláž, Š. (2009) · Chemical Reviews · doi:10.1021/cr030440j · Cited by 86
Hubal, E. A. C., Wetmore, B. A., Wambaugh, J. F., El-Masri, H. A., Sobus, J. R., & Bahadori, T. (2018) · Journal of Exposure Science & Environmental Epidemiology · doi:10.1038/s41370-018-0046-9 · Cited by 82
Estimating Screening-Level Organic Chemical Half-Lives in Humans
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The contribution of dermal exposure to the internal exposure of bisphenol A in man
Mielke, H., Partosch, F., & Gundert‐Remy, U. (2011) · Toxicology Letters · doi:10.1016/j.toxlet.2011.04.032 · Cited by 78
Poulin, P., & Haddad, S. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23090 · Cited by 66
“fup = (1 + Iw) ( 1 + Iwp ) × Fwp + Pnlw × Fnlp (5)”
InfluentialJoussen, A. M., Wolf, S., Kaiser, P. K., Boyer, D. S., Schmelter, T., Sandbrink, R., Zeitz, O., Deeg, G., Richter, A., Zimmermann, T., et al. (2018) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.13794 · Cited by 63
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Dołżonek, J., Cho, C.-W., Stepnowski, P., Markiewicz, M., Thöming, J., & Stolte, S. (2017) · Environmental Pollution · doi:10.1016/j.envpol.2017.04.079 · Cited by 57
“3 is based on BCFs of neutral (non-ionizable) organic compoundswhich can notably sorb to both phospholipids and storage lipids, whereas ionised compounds predominantly sorb to phospholipids (Endo et al., 2011; Escher et al., 2000b; Schmitt, 2008).”
BackgroundIwata, H., Matsuo, T., Mamada, H., Motomura, T., Matsushita, M., Fujiwara, T., Maeda, K., & Handa, K. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c00318 · Cited by 60
Graham, H., Walker, M., Jones, O., Yates, J. W. T., Galetin, A., & Aarons, L. J. (2011) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.2011.01429.x · Cited by 57
Bury, D., Alexander‐White, C., M.A., H. J. C. I., Cronin, M., Desprez, B., Detroyer, A., Efremenko, A. Y., Firman, J. W., Hack, E., Hewitt, N. J., et al. (2021) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2021.104931 · Cited by 61
“Tissue:blood partition coefficients (PC) were estimated by Gajewska et al. (2015) using the algorithm of Schmitt (2008), except for skin.”
MethodInfluentialRuark, C. D., Hack, C. E., Robinson, P. J., Mahle, D. A., & Gearhart, J. M. (2014) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24011 · Cited by 54
“Researchers suggest that active transport may explain deviations of mechanistic Kt:pl model predictions from observed Kt:pl.1,2,11,21 The mechanistic Kt:pl model described herein, for the calculation of KTotalt:pl , is the first to include both passive and active transport mechanisms, such as p-glycoprotein (P-gp) eff…”
BackgroundSchug, M., Stöber, R. M., Heise, T., Mielke, H., Gundert‐Remy, U., Godoy, P., Reif, R., Blaszkewicz, M., Ellinger-Ziegelbauer, H. C., Ahr, H.-J., et al. (2012) · Archives of Toxicology · doi:10.1007/s00204-012-0999-8 · Cited by 50
Caldwell, J. C., Evans, M. V., & Krishnan, K. (2012) · Journal of Toxicology · doi:10.1155/2012/852384 · Cited by 51
“, [35, 36]) are likely to facilitate more elegant implementation of the in vitro to in vivo paradigms.”
BackgroundNajjar, A., Punt, A., Wambaugh, J. F., Paini, A., Ellison, C. A., Fragki, S., Bianchi, E., Zhang, F., Westerhout, J., Mueller, D., et al. (2022) · Archives of Toxicology · doi:10.1007/s00204-022-03356-5 · Cited by 50
Lu, J., Goldsmith, M., Grulke, C., Chang, D. T., Brooks, R. D., Leonard, J. A., Phillips, M. B., Hypes, E. D., Fair, M. J., Tornero‐Velez, R., et al. (2016) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004495 · Cited by 50
“Studies have shown that not all structural properties are associated with chemicals’ PK properties [2,3,45–48].”
BackgroundQSARs for PBPK modelling of environmental contaminants
Peyret, T., & Krishnan, K. (2011) · SAR and QSAR in environmental research · doi:10.1080/1062936x.2010.548351 · Cited by 52
“Most of the refinements of the PC algorithms as well as QSARs for binding to albumin have been accomplished based on data for pharmaceutical substances [65,74–76,87–97].”
MethodLautz, L. S., Nebbia, C., Hoeks, S., Oldenkamp, R., Hendriks, A. J., Ragas, A. M. J., & Dorne, J. L. C. M. (2020) · Environment International · doi:10.1016/j.envint.2020.105488 · Cited by 48
Evaluation and calibration of high-throughput predictions of chemical distribution to tissues
Pearce, R. G., Setzer, R. W., Davis, J. L., & Wambaugh, J. F. (2017) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-017-9548-7 · Cited by 50
“The partition coefficients for all components of a cell are summed together to calculate the cell:cell water partition coefficient [22]:”
BackgroundMethodInfluentialZake, D. M., Kurlovičs, J., Zaharenko, L., Komašilovs, V., Kloviņš, J., & Stalidzāns, E. (2021) · PLoS ONE · doi:10.1371/journal.pone.0249594 · Cited by 50
“The organs and tissues are connected via arterial and venous blood flow joined in the lungs [22, 23].”
BackgroundMethodUpdate and Evaluation of a High-Throughput In Vitro Mass Balance Distribution Model: IV-MBM EQP v2.0
Armitage, J. M., Sangion, A., Parmar, R., Looky, A., & Arnot, J. A. (2021) · Toxics · doi:10.3390/toxics9110315 · Cited by 54
“, octanol-water partition ratio), (iv) ability to simulate ionizable organic chemicals (IOCs, monoprotic acids and bases), (v) ability to distinguish between sorption to anionic phospholipids and neutral phospholipids for IOCs [27], (vi) preliminary approach to simulate lysosomal sequestration (“ion trapping”) for bas…”
BackgroundSettimo, L., & Taylor, D. M. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881117742101 · Cited by 45
“This was expected since trazodone is a basic lipophilic compound, thus this compound is predicted to bind to fat tissues and membranes (Schmitt, 2008).”
Utsey, K., Gastonguay, M. S., Russell, S., Freling, R., Riggs, M. M., & Elmokadem, A. (2020) · Drug Metabolism and Disposition · doi:10.1124/dmd.120.090498 · Cited by 46
“Schmitt considered a universal method that separated tissues into water, neutral lipids, neutral and acidic phospholipids, and protein fractions (Schmitt, 2008).”
MethodInfluentialPradeep, P., Patlewicz, G. Y., Pearce, R., Wambaugh, J. F., Wetmore, B. A., & Judson, R. (2020) · Computational Toxicology · doi:10.1016/j.comtox.2020.100136 · Cited by 45
Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus)
Leavens, T. L., Tell, L. A., Kissell, L. W., Smith, G., Smith, D. J., Wagner, S., Shelver, W. L., Wu, H., Baynes, R. E., & Riviere, J. E. (2014) · Food Additives & Contaminants Part A · doi:10.1080/19440049.2014.938363 · Cited by 44
A Comprehensive Framework for Physiologically‐Based Pharmacokinetic Modeling in Matlab
Stader, F., Penny, M. A., Siccardi, M., & Marzolini, C. (2019) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12399 · Cited by 45
“41 Poulin and Theil 36,37 assume homogenous distribution in a tissue, which does not hold true if the cell membrane is a tight barrier.”
BackgroundYun, Y. E., & Edginton, A. N. (2013) · Xenobiotica · doi:10.3109/00498254.2013.770182 · Cited by 43
“Further modifications to the model were made by Schmitt (2008), who accounted for the combination of the effects of the drug distribution in the interstitial space, the effects of the pH gradient between the plasma and the tissues, the partitioning into the different lipid components in the tissues…”
BackgroundMethodInfluentialKovar, L., Schräpel, C., Selzer, D., Kohl, Y., Bals, R., Schwab, M. G., & Lehr, T. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12060578 · Cited by 41
Nauwelaerts, N., Deferm, N., Smits, A., Bernardini, C., Lammens, B., Gandia, P., Panchaud, A., Nordeng, H., Bacci, M. L., Forni, M., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111038 · Cited by 46
Uptake and depuration of eight fluoroquinolones (FQs) in common carp (Cyprinus carpio)
Chen, M., Zhao, H., Wang, Y., Bekele, T. G., Liu, W., & Chen, J. (2019) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2019.04.075 · Cited by 40
PBPK in Preterm and Term Neonates: A Review
Michelet, R., Bocxlaer, J. V., & Vermeulen, A. (2017) · Current Pharmaceutical Design · doi:10.2174/1381612823666171009143840 · Cited by 39
Zhang, Z., Wang, S., & Li, L. (2021) · Environmental Science Processes & Impacts · doi:10.1039/d1em00252j · Cited by 36
Influence of physicochemical parameters on PPCP occurrences in the wetlands
Ohoro, C. R., Adeniji, A., Elsheikh, E. A. E., Al-Marzouqi, A., Otim, M., Okoh, O., & Okoh, A. (2022) · Environmental Monitoring & Assessment · doi:10.1007/s10661-022-09990-x · Cited by 32
“(2005) and Schmitt (2008), Karnjanapiboonwong et al.”
Nabi, D., & Arey, J. S. (2017) · Environmental Science & Technology · doi:10.1021/acs.est.6b05071 · Cited by 37
Poulin, P. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24427 · Cited by 37
Bessems, J. G. M., Paini, A., Gajewska, M., & Worth, A. P. (2017) · Toxicology · doi:10.1016/j.tox.2017.03.012 · Cited by 36
“We used the QSAR-based Schmitt approach to calculate a partition between the blood and the organs of interest (Schmitt, 2008).”
MethodAntontsev, V. G., Jagarapu, A., Bundey, Y., Hou, H., Khotimchenko, M., Walsh, J., & Varshney, J. (2021) · Scientific Reports · doi:10.1038/s41598-021-90637-1 · Cited by 34
Smith, J. N., Hinderliter, P. M., Timchalk, C. A., Bartels, M. J., & Poet, T. S. (2013) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2013.10.005 · Cited by 34
Jia, X., Teutonico, D., Dhakal, S., Psarellis, Y. M., Abós, A., Zhu, H., Mavroudis, P. D., & Pillai, N. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00340 · Cited by 38
Hines, D. E., Bell, S. M., Chang, X., Mansouri, K., Allen, D., & Kleinstreuer, N. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.864742 · Cited by 35
“For example, metabolism parameters such as intrinsic clearance (Obach, 2011; OECD, 2018), plasma protein fraction unbound (Poulin, Burczynski and Haddad, 2016; Hartung, 2018), and tissue-specific partition coefficients (Schmitt, 2008) are necessary and chemical structure-dependent.”
BackgroundAllendorf, F., Goss, K., & Ulrich, N. (2020) · Environmental Toxicology and Chemistry · doi:10.1002/etc.4954 · Cited by 34
“Albumin as a component of the interstitium is usually not considered in physiologically based models for other compounds (Schmitt 2008; Ruark et al. 2014) but could be of relevance because of the high sorption capacity of albumin for PFAAs (Cheng and Ng 2017).”
BackgroundResultInfluentialGeci, R., Gadaleta, D., de Lomana, M. G., Ortega-Vallbona, R., Colombo, E., Serrano‐Candelas, E., Paini, A., Kuepfer, L., & Schaller, S. (2024) · Archives of Toxicology · doi:10.1007/s00204-024-03764-9 · Cited by 35
“The five tested partitioning methods available in PK-Sim were PK-Sim (Willmann et al. 2005), Schmitt (2008), Rodgers and Rowland (2006), Poulin and Theil (2002), and Berezhkovskiy (2004).”
Punt, A., Louisse, J., Pinckaers, N. E. T., Fabian, E. J., & van Ravenzwaay, B. (2021) · Toxicological Sciences · doi:10.1093/toxsci/kfab150 · Cited by 32
“Input Approaches Applied in the PBK Model Predictions Applied Input Method Reference Method Name Used in the Figures Number of Compounds for Which the Respective Data Are Available Intestinal uptake (ka and fa) QSAR based on the topological surface area (TPSA) Hou et al. (2004) QSAR 44 Caco-2 Papp This work In vitro 2…”
InfluentialTissue lipids and drug distribution: Dog versus rat
Rodgers, T., Jones, H. M., & Rowland, M. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23285 · Cited by 31
Fendt, R., Hofmann, U., Schneider, A. R. P., Schaeffeler, E., Burghaus, R., Yılmaz, A., Blank, L. M., Kerb, R., Lippert, J., Schlender, J., et al. (2021) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12646 · Cited by 30
The enrofloxacin pollution control from fish to environment
Xi, F. (2023) · Marine Pollution Bulletin · doi:10.1016/j.marpolbul.2023.115923 · Cited by 30
Yang, X., Morris, S. M., Gearhart, J. M., Ruark, C. D., Paule, M. G., Slikker, W., Mattison, D. R., Vitiello, B., Twaddle, N. C., Doerge, D. R., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106101 · Cited by 30
“Tissue-to-plasma partition coefficients for MPH were estimated using a mechanistic model [61] based on tissue composition and compound specific parameters.”
MethodRobust PBPK/PD-Based Model Predictive Control of Blood Glucose
Schaller, S., Lippert, J., Schaupp, L. A., Pieber, T. R., Schuppert, A., & Eißing, T. (2015) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2015.2497273 · Cited by 29
“A more in-depth description is provided in a published description of a workshop [47]; this provides insight into the essential structural elements and theoretical concepts that underlie a PBPK model, with additional in-depth technical detail in [48]–[50] and detail on the database in [51].”
BackgroundDaily uptake of mycotoxins – TDI might not be protective for nursed infants
Degen, G. H., Partosch, F., Muñoz, K., & Gundert‐Remy, U. (2017) · Toxicology Letters · doi:10.1016/j.toxlet.2017.06.002 · Cited by 30
Methods to Predict Volume of Distribution
Holt, K., Nagar, S., & Korzekwa, K. (2019) · Current Pharmacology Reports · doi:10.1007/s40495-019-00186-5 · Cited by 30
Lautz, L. S., Hoeks, S., Oldenkamp, R., Hendriks, A. J., Dorne, J. L. C. M., & Ragas, A. M. J. (2019) · Toxicology Letters · doi:10.1016/j.toxlet.2019.10.008 · Cited by 30
Fischer, F. C., Thackray, C. P., Ferguson, N., Chicoine, C., Skende, O., Hu, Z., Zhu, Y., Slitt, A., & Sunderland, E. M. (2025) · Environmental Science & Technology · doi:10.1021/acs.est.5c05473 · Cited by 31
Yau, E., Olivares‐Morales, A., Gertz, M., Parrott, N. J., Darwich, A. S., Aarons, L. J., & Ogungbenro, K. (2020) · The AAPS Journal · doi:10.1208/s12248-020-0418-7 · Cited by 28
Fairman, K., Li, M., Ning, B., & Lumen, A. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114468 · Cited by 31
Trazodone: a multifunctional antidepressant. Evaluation of its properties and real-world use
Cuomo, A., Bianchetti, A., Cagnin, A., Berardis, D. D., Fazio, I. D., Incalzi, R. A., Marra, C., Neviani, F., & Nicoletti, F. (2021) · Journal of Gerontology and Geriatrics · doi:10.36150/2499-6564-n320 · Cited by 31
Ye, M., Luo, X., Liu, Y., Zhu, C., Feng, Q.-J., Zeng, Y., & Mai, B. (2023) · Environmental Science & Technology · doi:10.1021/acs.est.2c09063 · Cited by 29
Yun, Y. E., Cotton, C. A., & Edginton, A. N. (2013) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-013-9342-0 · Cited by 28
Kovar, L., Weber, A., Zemlin, M., Kohl, Y., Bals, R., Meibohm, B., Selzer, D., & Lehr, T. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12100908 · Cited by 28
Metadata
- Authors
- Schmitt, W.
- Affiliations
- Bayer (Germany) (DE)
- Corresponding author
- Schmitt, Walter
- ORCID
- Schmitt, Walter
- Venue
- Toxicology in Vitro
- Publisher
- Elsevier BV
- Published
- 2008-03
- Volume
- 22
- Issue
- 2
- Pages
- 457-467
- ISSN
- 0887-2333 (ISSN-L)
- OpenAlex
- W2026015795
- Cited by
- 349
- References
- 38
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 19 · 2023: 34 · 2022: 39 · 2021: 33 · 2020: 20 · 2019: 20 · 2018: 16 · 2017: 25 · 2016: 15 · 2015: 14 · 2014: 13 · 2013: 16 · 2012: 17
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology in Vitro (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- tissue-to-plasma partition coefficient, organic compounds, lipophilicity, tissue composition, pKa, drug compounds, mechanistic model, erythrocytes
- MeSH terms
- Algorithms, Animals, Chemistry, Physical, Hydrogen-Ion Concentration, Lipids, Phospholipids, Plasma, Proteins, Tissue Distribution, Models, Statistical, Xenobiotics, Extracellular Fluid, Rats, Chemical Phenomena
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