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General approach for the calculation of tissue to plasma partition coefficients

Schmitt, Walter·2008·Toxicology in Vitro

DOI 10.1016/j.tiv.2007.09.010

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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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“Next, a naïve oral model was set up for a mean male individual weighing 71 kg. Rodgers and Rowland [28–30] and Schmitt [31] prediction methods for partition coefficients were evaluated based on visual model performance for curve shape.”
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Ni, L., Cao, Z., Jiang, J., Zhang, W., Hu, W. M., Zhang, Q., Shen, C., Chen, X., & Zheng, L. (2024) · Pharmaceuticals · doi:10.3390/ph17050640 · Cited by 4
“For hydrocodone, partition coefficients and cell permeability parameters were estimated using Schmitt and Charge-dependent Schmitt normalized to PK-Sim methods, respectively [33].”
Method
In Vitro Approaches to Predictive Biokinetics
Blaauboer, B. J. (2014) · Methods in pharmacology and toxicology · doi:10.1007/978-1-4939-0521-8_23 · Cited by 5
Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling of Countermeasures to Nerve Agents
Merrill, E. A., Ruark, C., Gearhart, J. M., & Robinson, P. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-800159-2.00069-5 · Cited by 4
Effect of dose and exposure protocol on the toxicokinetics and first-pass elimination of trichloroethylene and 1,1,1-trichloroethane
Mortuza, T. B., Muralidhara, S., White, C. A., Cummings, B. S., Hines, C., & Bruckner, J. V. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.09.043 · Cited by 4
“The total lipid content of the liver is even lower, and its proportion of phospholipids higher than in brain (Schmitt, 2008).”
BackgroundInfluential
Letter to the Editor
Mielke, H., Partosch, F., & Gundert‐Remy, U. (2019) · Archives of Toxicology · doi:10.1007/s00204-019-02421-w · Cited by 4
“Technically, a mechanistically based algorithm for the calculation of the tissue/blood(plasma) concentration (e.g., Schmitt 2008) is important for a meaningful modelling.”
Development, testing, parameterisation, and calibration of a human PBK model for the plasticiser, di (2-ethylhexyl) adipate (DEHA) using in silico, in vitro and human biomonitoring data
McNally, K., Sams, C., & Loizou, G. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1165770 · Cited by 4
“The algorithm of Poulin and Haddad (2012) was implemented as a Microsoft® Excel Add-in whereas a modified version of the algorithm of Schmitt (2008) was available within the httk: R Package for High-Throughput Toxicokinetics (Pearce et al., 2017).”
MethodInfluential
Enabling transparent toxicokinetic modeling for public health risk assessment
Davidson-Fritz, S. E., Ring, C., Evans, M. V., Schacht, C. M., Chang, X., Breen, M., Honda, G. S., Kenyon, E. M., Linakis, M. W., Meade, A. E., et al. (2025) · PLoS ONE · doi:10.1371/journal.pone.0321321 · Cited by 3
Oligosaccharide Lactate Nanoparticles Enhance Tissue Targeting: A Case Study of the Controlled Delivery of Bedaquiline to Cardiac Tissue in TB Pericarditis
Ayodele, S., Kumar, P., Eyk, A. D. V., van der Bijl, P., & Choonara, Y. E. (2025) · Molecules · doi:10.3390/molecules30132845 · Cited by 3
“…across the tissue to date, but studies on other tissues in the body have reported that the permeability coefficient and log P demonstrate a proportional relationship [48]; therefore, a compound with a high log P (more lipophilic molecule) value is expected to permeate the pericardium better.”
Comparison of physiologically based pharmacokinetic modeling platforms for developmental neurotoxicity in vitro to in vivo extrapolation
Kreutz, A., Chang, X., Lawless, M. S., Proença, S., Schaller, S., Kleinstreuer, N., & Högberg, H. T. (2025) · Toxicological Sciences · doi:10.1093/toxsci/kfaf147 · Cited by 5
“By default, GastroPlus uses the Lucakova (Rodgers-single) method, and httk uses the Schmitt method (Rodgers et al. 2005; Rodgers and Rowland 2006; Schmitt 2008).”
Physiologically based pharmacokinetic model: distribution processes
Ruark, C. D. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818596-4.00006-0 · Cited by 3
Computational Amendment of Parenteral In Situ Forming Particulates’ Characteristics: Design of Experiment and PBPK Physiological Modeling
Hoffy, N. M. E., Yacoub, A. S., Ghoneim, A. M., Ibrahim, M. M., Ammar, H. O., & Eissa, N. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15102513 · Cited by 3
“Cellular permeabilities and partition coefﬁcients were computed as Schmitt and PK-Sim ® standard methods, respectively [34,35].”
Method
Physiologically-based pharmacokinetic modeling after drug inhalation
Himstedt, A., Bäckman, P., & Borghardt, J. M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814974-4.00009-2 · Cited by 3
A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the insecticide dimethoate
Reiss, R., Loccisano, A. E., Deines, A. M., Kim, M., Nallani, G. C., Chandrasekaran, A., & Whatling, P. (2023) · Xenobiotica · doi:10.1080/00498254.2023.2258507 · Cited by 3
“Partition coefficients were estimated using the httk R package (https://www.rdocumentation.org/packages/httk/versions/1.9.2), which uses the Schmitt (2008) method.”
MethodInfluential
Salivary therapeutic monitoring of methadone toxicity in neonates after transplacental transfer from parturient mothers treated with oral methadone guided by PBPK modeling
Alsmadi, M. M. (2023) · Computational Toxicology · doi:10.1016/j.comtox.2023.100296 · Cited by 3
Rapid determination of serum albumin partition coefficients using affinity chromatography
Ulrich, N., & Böhme, A. (2022) · Environmental Advances · doi:10.1016/j.envadv.2022.100284 · Cited by 3
Integrated Translation Framework for Endocrine Disruptors in the area of Computational Toxicology
Kumar, V., Deepika, D., & Sharma, R. P. (2020) · Royal Society of Chemistry eBooks · doi:10.1039/9781839160738-00080 · Cited by 3
Predicting partitioning from low density polyethylene to blood and adipose tissue by linear solvation energy relationship models
Ulrich, N., Böhme, A., Strobel, A. B., & Egert, T. (2023) · Journal of Biomedical Materials Research Part B Applied Biomaterials · doi:10.1002/jbm.b.35304 · Cited by 3
Pharmacokinetics and PBPK Models
Fisher, J. W., Wang, J., Duan, P., & Yang, X. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.64919-x · Cited by 3
The Need for Human Exposure Projection in the Interpretation of PreclinicalIn VitroandIn VivoADME Tox Data
Poulin, P. (2016) · Wiley eBooks · doi:10.1002/9781119053248.ch6 · Cited by 3
Structure–Tissue Exposure/Selectivity Relationship (STR) on Carbamates of Cannabidiol
Wang, S., Yang, J.-G., Rong, K., Li, H., Wu, C., & Tang, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252211888 · Cited by 2
Physiologically based pharmacokinetic (PBPK) modeling of gliclazide for different genotypes of CYP2C9 and CYP2C19
Park, H.-J., Lee, S., Kang, P., Cho, C., Jang, C., Lee, Y. J., Lee, Y. J., Bae, J., & Choi, C. (2025) · Archives of Pharmacal Research · doi:10.1007/s12272-024-01528-8 · Cited by 2
“Estimation methods for the partition coefficients and cellular permeabilities were Schmitt and Charge dependent Schmitt normalized to PK-Sim ® (Schmitt 2008; Hindmarsh et al. 2023), respectively.”
Influential
Translational Pharmacokinetic-Pharmacodynamic Modeling of a Novel Oral Dihydroorotate Dehydrogenase (DHODH) Inhibitor, HOSU-53 (JBZ-001)
Na, J. Y., Hai, M., Kim, K., Vibhute, S. M., Bennett, C. E., Coss, C. C., & Phelps, M. A. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17040412 · Cited by 2
“IC 90 for inhibition of DHODH was determined from in vitro cell-free DHODH inhibition assay to be 669 pM, which was subsequently used as a target for steady-state intracellular hepatocyte concentrations, as DHODH is primarily expressed in liver tissue in healthy human populations [26,27].”
Collaborative evaluation of in silico predictions for high throughput toxicokinetics
Wambaugh, J. F., Sipes, N. S., Mercado, G. P., Arnot, J. A., Bertato, L., Brown, T. N., Chirico, N., Cook, C., Dawson, D. E., Davidson-Fritz, S. E., et al. (2025) · Toxicology in Vitro · doi:10.1016/j.tiv.2025.106150 · Cited by 2
Application of in vitro to in vivo extrapolation (IVIVE) to inform chemical health guidance value derivation—sample case studies comparing neuro-, hepato-, and developmental toxicities
Chang, X., Allen, D., Kleinstreuer, N., & Mumtaz, M. M. (2026) · Toxicological Sciences · doi:10.1093/toxsci/kfag017 · Cited by 2
A cross-species comparison of antiretroviral penetration into lymph nodes using novel physiologically based pharmacokinetic models
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Advancing ecotoxicological studies: Utilizing new approach methodologies to enable cross-species extrapolation and reduce avian testing
Wu, Y., Maul, J. D., Vaugeois, M., & Galić, N. (2024) · Environmental Pollution · doi:10.1016/j.envpol.2024.124765 · Cited by 2
Streamlining Linear Free Energy Relationships of Proteins through Dimensionality Analysis and Linear Modeling
Khawar, M. I., Arshad, M., Achterberg, E. P., & Nabi, D. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01289 · Cited by 2
Physiologically based pharmacokinetic coupled model of zonisamide to predict the exposure and dose exploration in maternal, fetal, and neonatal populations during pregnancy and postpartum
Li, Y., Liu, Z., Chen, Y., Wang, W., Chen, T., Li, S., Wu, Y., & Xie, H. (2025) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2025.103912 · Cited by 2
Computational Approaches for Developing Informative Prior Distributions for Bayesian Calibration of PBPK Models
Davis, J. L., Tornero‐Velez, R., & Setzer, R. W. (2012) · ACS symposium series · doi:10.1021/bk-2012-1099.ch018 · Cited by 2
Scientific Opinion of Flavouring Group Evaluation 411 (FGE.411): 2‐(4‐methylphenoxy)‐N‐(1H‐pyrazol‐3‐yl)‐N‐(thiophen‐2‐ylmethyl)acetamide from chemical group 30 (miscellaneous substances)
(FAF), E. P. O. F. A. A. F., Younes, M., Aquilina, G., Castle, L., Engel, K., Fowler, P., Fernández, M. J. F., Fürst, P., Gundert‐Remy, U., Gürtler, R., et al. (2018) · EFSA Journal · doi:10.2903/j.efsa.2018.5421 · Cited by 2
“Using the method of Schmitt (2008) to estimate blood-tissue partitioning coefficients, estimation of liver concentrations following acute exposure to the flavouring substance in humans, based on the use levels provided, gives a maximum liver concentration, which is lower than the lowest IC50…”
Method
Bisphenol A—toxicity and risk assessment update with academic and regulatory perspectives and physiologically based pharmacokinetic modeling
Fan, A. M., Chou, W.-C., & Lin, P. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-89773-0.00039-4 · Cited by 2
Applicability of generic PBK modelling in chemical hazard assessment: A case study with IndusChemFate
Fragki, S., Piersma, A. H., Westerhout, J., Kienhuis, A. S., Kramer, N. I., & Zeilmaker, M. J. (2022) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2022.105267 · Cited by 2
Comments on “A simple method for estimating in vitro air-tissue and in vivo blood–tissue partition coefficients” by Abraham, Gala, Ibrahim, Acree and Liu
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Report of the Synthesis and Integration of Epidemiological and Toxicological Evidence Subgroup (SETE) of the Committee on Toxicity and the Committee on Carcinogenicity
SETE Working Group of the COT, & COC (2021) · doi:10.46756/sci.fsa.sjm598 · Cited by 2
“…of steady state tissue:plasma partition coefficient (Peyret et al., 2010; Poulin and Haddad, 2012; Rodgers et al., 2005; Rodgers and Rowland, 2006; Schmitt, 2008) and the measurement in vitro of metabolism or clearance in isolated human cells has led to the development and application of “bottom…”
Background
Usages de la colistine en médecine humaine et vétérinaire : exploration pharmacocinétique et problématique d'antibiorésistance
Viel, A. (2017) · doi:10.70675/ad7235a1z0952z43f8zb9fczaab231dc4693 · Cited by 2
Development and specification of a toxicokinetic and toxicodynamic growth model of Myriophyllum spicatum for use in risk assessment
Heine, S., & Schäffer, A. (2014) · RWTH Publications (RWTH Aachen) · Cited by 2
Pharmacokinetics and PBPK Models During Pregnancy, Lactation, and Developmental Stages
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Prediction of SPT-07A Pharmacokinetics in Rats, Dogs, and Humans Using a Physiologically-Based Pharmacokinetic Model and In Vitro Data
Zhu, X., Kong, W., Wang, Z., Liu, X., & Liu, L. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16121596 · Cited by 1
Influence of polystyrene microplastics on bioconcentration and metabolism of 2-ethylhexyl diphenyl phosphate in common carp (Cyprinus carpio)
Zhong, Z., Wang, J., Zhao, H., Zhao, J., Bekele, T. G., Wan, H., Sun, Y., Li, X., & Zhang, X. (2025) · Journal of Environmental Sciences · doi:10.1016/j.jes.2025.10.027 · Cited by 1

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)
DOI: 10.1016/j.tiv.2007.09.010
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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General approach for the calculation of tissue to plasma partition coefficients

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