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 Kp values, the PK-Sim standard and Schmitt models can be applied in PK-Sim.
“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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“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., & D, K. H. M. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c00318 · Cited by 57 · see citing works
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 · see citing works
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 56 · see citing works
“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 · see citing works
“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 · see citing works
Caldwell, J. C., Evans, M. V., & Krishnan, K. (2012) · Journal of Toxicology · doi:10.1155/2012/852384 · Cited by 51 · see citing works
“, [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 · see citing works
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 · see citing works
“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 49 · see citing works
“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 · see citing works
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 · see citing works
“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 48 · see citing works
“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 46 · see citing works
“, 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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Zhang, Z., Wang, S., & Li, L. (2021) · Environmental Science Processes & Impacts · doi:10.1039/d1em00252j · Cited by 36 · see citing works
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 · see citing works
“(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 · see citing works
Poulin, P. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24427 · Cited by 37 · see citing works
Bessems, J. G. M., Paini, A., Gajewska, M., & Worth, A. P. (2017) · Toxicology · doi:10.1016/j.tox.2017.03.012 · Cited by 36 · see citing works
“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 · see citing works
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 · see citing works
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 37 · see citing works
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 · see citing works
“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 33 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
The enrofloxacin pollution control from fish to environment
Xi, F. (2023) · Marine Pollution Bulletin · doi:10.1016/j.marpolbul.2023.115923 · Cited by 30 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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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 29 · see citing works
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 · see citing works
Fairman, K., Li, M., Ning, B., & Lumen, A. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114468 · Cited by 29 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
- 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
- Physical Sciences › Computer Science › Computational Theory and Mathematics › 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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