Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction
Abstract
Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of drug-metabolising enzymes. In this review the authors describe similarities and differences in this respect among the different species, including man. This may be helpful for drug researchers to choose the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. The authors focus on CYPs, which are the main enzymes involved in numerous oxidative reactions and often play a critical role in the metabolism and pharmacokinetics of xenobiotics. In addition, induction and inhibition of CYPs are compared among species. The authors conclude that CYP2E1 shows no large differences between species, and extrapolation between species appears to hold quite well. In contrast, the species-specific isoforms of CYP1A, -2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans.
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The expressions and activities of drug-metabolizing enzymes are different in humans and animals.
“One of the main reasons is that the expressions and activities of drug-metabolizing enzymes are different in humans and animals.6)”
From Cryopreservation of Hepatocyte Organoid-Derived Cells Generated from Human iPS Cells (2025) · cites this paper as [6]
Cites
Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., & Guengerich, F. P. (1994) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)22379-5 · Cited by 2,785 · cited 5× · see citing works
“CYP2C19 proteins are primarily located in the liver where they account for approximately 20% of total cytochrome P450 [15].”
BackgroundInfluentialInterspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics
Boxenbaum, H. (1982) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01062336 · Cited by 648 · cited 1× · see citing works
“The methodology was applied to the prediction of plasma concentration–time profiles [3] and the main PK parameters (distribution volumes and clearances) [4], and a number of modifications were subsequently 1.”
MethodOrphan Nuclear Receptors: The Exotics of Xenobiotics
Xie, W., & Evans, R. M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.r100033200 · Cited by 210 · see citing works
COMPARISON OF MOUSE AND RAT CYTOCHROME P450-MEDIATED METABOLISM IN LIVER AND INTESTINE
Martignoni, M., Groothuis, G., & de Kanter, R. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.009035 · Cited by 101 · see citing works
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McGonigle, P., & Ruggeri, B. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.08.006 · Cited by 610 · see citing works
Bell, C. C., Dankers, A. C. A., Lauschke, V. M., Sison-Young, R., Jenkins, R., Rowe, C., Goldring, C. E., Park, K., Regan, S. L., Walker, T., et al. (2018) · Toxicological Sciences · doi:10.1093/toxsci/kfx289 · Cited by 327 · see citing works
Fan, J., & de Lannoy, I. A. M. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.09.007 · Cited by 309 · see citing works
Yamada, M., Utoh, R., Ohashi, K., Tatsumi, K., Yamato, M., Okano, T., & Seki, M. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.07.068 · Cited by 247 · see citing works
Hatton, G. B., Yadav, V., Basit, A. W., & Merchant, H. A. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24365 · Cited by 204 · see citing works
A lung/liver-on-a-chip platform for acute and chronic toxicity studies
Bovard, D., Sandoz, A., Luettich, K., Frentzel, S., Iskandar, A., Marescotti, D., Trivedi, K., Guedj, E., Dutertre, Q., Peitsch, M. C., et al. (2018) · Lab on a Chip · doi:10.1039/c8lc01029c · Cited by 195 · see citing works
Chang, E. T., Adami, H.-O., Boffetta, P., Cole, P., Starr, T. B., & Mandel, J. S. (2014) · Critical Reviews in Toxicology · doi:10.3109/10408444.2014.905767 · Cited by 180 · see citing works
Prantil-Baun, R., Novak, R., Das, D., Somayaji, M. R., Przekwas, A., & Ingber, D. E. (2018) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-104748 · Cited by 176 · see citing works
Li, C. Y., Stevens, K. R., Schwartz, R. E., Alejandro, B. S., Huang, J. H., & Bhatia, S. N. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2013.0667 · Cited by 132 · see citing works
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Ehrlich, A., Duche, D., Ouedraogo, G., & Nahmias, Y. (2019) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-060418-052305 · Cited by 125 · see citing works
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Kang, Y. B., Eo, J., Mert, S., Yarmush, M. L., & Usta, O. B. (2018) · Scientific Reports · doi:10.1038/s41598-018-27179-6 · Cited by 122 · see citing works
Rodenhizer, D., Dean, T., D'Arcangelo, E., & McGuigan, A. P. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201701174 · Cited by 80 · see citing works
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Greek, R., Pippus, A., & Hansen, L. A. (2012) · BMC Medical Ethics · doi:10.1186/1472-6939-13-16 · Cited by 78 · see citing works
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Miller, C. P., Shin, W., Ahn, E. H., Kim, H. J., & Kim, D.-H. (2020) · Trends in biotechnology · doi:10.1016/j.tibtech.2020.01.003 · Cited by 74 · see citing works
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The effects of fasting on drug metabolism
Lammers, L. A., Achterbergh, R., Mathôt, R. A. A., & Romijn, J. A. (2020) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2020.1706728 · Cited by 32 · see citing works
Psychophysiological stress: a significant parameter in drug pharmacokinetics
Konstandi, M. (2013) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2013.816283 · Cited by 31 · see citing works
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Ralvenius, W. T., Mungenast, A. E., Woolf, H., Huston, M. M., Gillingham, T. Z., Godin, S. K., Penney, J., Cam, H. P., Gao, F., Fernandez, C. G., et al. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20222105 · Cited by 31 · see citing works
Age-related Changes in the Energy of Human Mesenchymal Stem Cells
Barilani, M., Lovejoy, C., Piras, R., Abramov, A. Y., Lazzari, L., & Angelova, P. R. (2022) · Journal of Cellular Physiology · doi:10.1002/jcp.30638 · Cited by 31 · see citing works
Wright, P. S. R., Briggs, K. A., Thomas, R., Smith, G. F., Maglennon, G., Mikulskis, P., Chapman, M., Greene, N., Phillips, B. U., & Bender, A. (2023) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2022.105308 · Cited by 8 · see citing works
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Nagai, W., Inui, J., Ueyama-Toba, Y., Asano, R., & Mizuguchi, H. (2025) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b25-00276 · Cited by 1 · see citing works
- Authors
- Martignoni, M., Groothuis, G. M. M., & de Kanter, R.
- Affiliations
- Nerviano Medical Sciences (IT)
- University of Groningen (NL)
- ORCID
- Groothuis, Geny M M
- Venue
- Expert Opinion on Drug Metabolism & Toxicology
- Publisher
- Informa UK Limited
- Published
- 2006-11-24
- Volume
- 2
- Issue
- 6
- Pages
- 875-894
- ISSN
- 1742-5255 (ISSN-L)
- 1744-7607
- OpenAlex
- W2096565553
- Cited by
- 1,478
- References
- 4
- Citations by year
- 2026: 95 · 2025: 108 · 2024: 85 · 2023: 76 · 2022: 99 · 2021: 126 · 2020: 122 · 2019: 87 · 2018: 93 · 2017: 87 · 2016: 103 · 2015: 83 · 2014: 62 · 2013: 54 · 2012: 68
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Opinion on Drug Metabolism & Toxicology (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- cytochrome P450, species differences, drug metabolism, cytochrome P450 induction, cytochrome P450 inhibition, animal models, CYP2E1, CYP1A, CYP2C, CYP2D, CYP3A, xenobiotic metabolism, pharmacokinetics
- MeSH terms
- Animals, Haplorhini, Cytochrome P-450 Enzyme System, Dogs, Pharmaceutical Preparations, Humans, Isoenzymes, Inactivation, Metabolic, Species Specificity, Mice, Rats
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