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Influence of CYP3A5 polymorphism on the pharmacokinetics of psychiatric drugs
Abstract
BACKGROUND: The contribution of the CYP3A5 enzyme to the metabolism of clinically used drugs has been established only for a few CYP3A substrates, such as the immunosuppressant tacrolimus, while for drugs used in the field of psychiatry its role is still vague. METHODS: We herein discuss all published data on the contribution of CYP3A5 and its polymorphisms to the metabolism of antipsychotics and antidepressants that are known to be metabolized by CYP3A enzymes, as well as of carbamazepine, an antiepileptic drug used as mood stabilizer. Published papers from 1990 to April 2015 were retrieved from PubMed and Scopus by use of the keywords CYP3A5, CYP3A, gene polymorphism, antipsychotics, psychiatry, pharmacogenomics, haloperidol, risperidone, quetiapine, aripiprazole, clozapine, olanzapine, antidepressants, and carbamazepine. RESULTS: Available evidence is only sparse and no firm conclusions can be drawn on whether CYP3A5 enzyme exhibits affinity and metabolic capacity similar to CYP3A4 for these drugs. Nevertheless, the role of CYP3A5 should be studied further, since there is evidence suggesting that CYP3A5 potentially catalyses alternative metabolic pathways that may give rise to intermediate metabolites with yet unknown pharmacologic properties and may also limit drug bioavailability through intestinal first pass metabolism. Additionally, expression of CYP3A5 may overcome CYP3A4 drug-drug interactions. CONCLUSIONS: Overall, CYP3A5 is an overlooked polymorphic enzyme and its potential in improving psychiatric pharmacogenomics remains to be explored. The impact of CYP3A5 pharmacogenetics in the clinical setting merits the attention of both researchers and clinicians.
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“For orally administered drugs absorbed in the gastrointestinal tract, the drug first passes through the liver and intestines before reaching systemic circulation [25–27].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [27]
In the citing paper
“CYP enzymes and P-glycoprotein (P-gp) are also expressed in the intestines, which may further lower systemic concentrations [26, 27].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [27]
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Correll, C. U., Kim, E., Sliwa, J. K., Hamm, W., Gopal, S., Mathews, M., Venkatasubramanian, R., & Saklad, S. R. (2021) · CNS Drugs · doi:10.1007/s40263-020-00779-5 · Cited by 205
Kloosterboer, S. M., de Winter, B. C. M., Reichart, C. G., Kouijzer, M. E. J., de Kroon, M. M. J., van Daalen, E., Ester, W. A., Rieken, R., Dieleman, G. C., van Altena, D., et al. (2020) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14465 · Cited by 79
“The influence of polymorphisms in other cytochrome P450 enzymes CYP3A4, CYP3A5 and the transport protein PGP on risperidone concentrations has not been previously studied in children and adolescents, despite evidence for this influence in adults.(50,51) Our study is the first to examine these polymorphisms for risperi…”
BackgroundEconomic evaluation in psychiatric pharmacogenomics: a systematic review
Karamperis, K., Koromina, M., Papantoniou, P., Σκώκου, Μ., Kanellakis, F., Mitropoulos, K. A., Vozikis, A., Müller, D. J., Patrinos, G. P., & Mitropoulou, C. (2021) · The Pharmacogenomics Journal · doi:10.1038/s41397-021-00249-1 · Cited by 68
Wang, D., Schneider-Thoma, J., Siafis, S., Qin, M., Wu, H., Zhu, Y., Davis, J. M., Priller, J., & Leucht, S. (2024) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2024.03.003 · Cited by 44
“LAIs do not undergo the first-pass effect in the liver enhancing bioavailability (Ragia et al., 2016), and their slower absorption and steadier blood concentrations might cause fewer side effects and provide better tolerance (Sheehan et al., 2012; Wang et al., 2023).”
BackgroundSychev, D. A., Zastrozhin, M. S., Мирошниченко, И. И., et al. (2017) · Drug Metabolism and Personalized Therapy · doi:10.1515/dmpt-2017-0021 · Cited by 22
“In addition, CYP3A5 expression may overcome CYP3A4 drug interaction [17].”
BackgroundQuantitative Prediction of CYP3A4‐ and CYP3A5‐Mediated Drug Interactions
Guo, Y., Lucksiri, A., Dickinson, G. L., et al. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1596 · Cited by 22
The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction
Застрожин, М. С., Гришина, Е. А., Ryzhikova, K. A., et al. (2017) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s144503 · Cited by 14
“Besides, the expression of CYP3A5 can inhibit CYP3A4 drug–drug interaction.(10) The primary purpose of this investigation was to estimate the relationship between CYP3A5 gene polymorphism, the activity of the CYP3A isoenzyme, and the risk of development of ADRs by haloperidol in patients with alcohol addiction.”
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Ragia, G., & Manolopoulos, V. G. (2022) · Pharmacogenomics · doi:10.2217/pgs-2022-0145 · Cited by 10
Self-citationChan, T. S., Byer-Alcorace, A. J., Latli, B., et al. (2023) · Pharmaceutical Research · doi:10.1007/s11095-023-03530-z · Cited by 9
“These data suggest that CYP3A5 polymorphisms, which have been a safety concern for psychiatric drugs due to the potential formation of toxic or pharmacologically active metabolites [9], should not be a concern for iclepertin.”
BackgroundZong, H., Zhang, Y., Liu, F., et al. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1458838 · Cited by 8
Abumiya, M., Takahashi, N., Yoshioka, T., et al. (2020) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.13257 · Cited by 6
Song, H.-Y., Xia, J.-S., Chen, Y., & Chen, L. (2022) · Human & Experimental Toxicology · doi:10.1177/09603271221080236 · Cited by 7
“CYP3A5 polymorphism can alter the pharmacokinetics and pharmacodynamics of some drugs, including anticancer agents and antihypertensive drugs.(8) Previous study has reported that the allelic frequencies of CYP3A5*2 (2480 G>A, 0.”
BackgroundAbdyrakhmanova, A. K., & Nasyrova, R. F. (2022) · Personalized Psychiatry and Neurology · doi:10.52667/2712-9179-2022-2-1-81-88 · Cited by 6
Ezzeldin, E., Tammam, M. H., & Abo-Talib, N. F. (2017) · International Journal of Analytical Chemistry · doi:10.1155/2017/1271383 · Cited by 6
“Combined drugs containing risperidone may also be used in depression treatment [2].”
BackgroundRole of cytochrome P450 enzymes in fimasartan metabolism in vitro
Choi, Y. J., Lee, J.-Y., Ryu, C. S., et al. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.03.036 · Cited by 6
Lock, S. K., Kappel, D. B., Owen, M. J., Walters, J., O’Donovan, M. C., Pardiñas, A. F., & Legge, S. E. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105745 · Cited by 5
“CYP3A5 is relatively under-examined in antipsychotic research 91 and its main genotype that leads to slower metabolism (*1/*3) is common world-wide but particularly in European populations.”
A Dual Functional Probe for Assessing Human CYP450 3A5 and 3A Enzymes Bioactivities
Yan, F., Cui, Y., An, Y., et al. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0173 · Cited by 3
Ün, İ., Barlas, O., Uyar, N., et al. (2018) · Turkish Journal of Biochemistry · doi:10.1515/tjb-2017-0226 · Cited by 2
“Although it has been reported that CYP3A5 is an overlooked polymorphic enzyme, its allelic frequency in specific ethnic groups is important to optimize pharmacotherapy [12, 26].”
BackgroundСпасов, А. А., Grechko, O. Y., Eliseeva, N. V., Lifanova, Y. V., & Aleksandrenkova, A. A. (2021) · Research Results in Pharmacology · doi:10.3897/rrpharmacology.7.68025 · Cited by 2
“At the same time, a decrease in the severity of the analgesic effect after 90 minutes when taken together with the kappa agonist – compound RU-1205, may be associated with the pharmacokinetic characteristics of the substances (Rashchenko 2014; Ragia et al. 2016).”
BackgroundIvashchenko, D. V., Che, M. D., Викторович, Ш. П., Kondratieva, R. V., Shubin, A. V., Aisin, F. R., Gragyants, B. R., Николаевна, Т. С., Денисенко, Н. П., Mirzaev, K. B., et al. (2025) · Meditsinskiy sovet = Medical Council · doi:10.21518/ms2025-246 · Cited by 1
Design, synthesis and evaluation of trofinetide prodrug based on diketopiperazine strategy
Feng, X., Dong, Y., Guo, C., Lu, J., Xu, Z., Bian, J., Peng, W., Luo, T., & Feng, J. (2026) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2026.118633 · Cited by 1
A gyógyszer-metabolizáló képességhez igazított pszichofarmakoterápia lehetőségei
Tóth, K. (2017) · Eötvös Loránd Tudományegyetem · doi:10.15476/elte.2017.111
Song, H.-Y., Xia, J.-S., Chen, Y., & Chen, L. (2021) · Human & Experimental Toxicology · doi:10.1177/09603271211052989
“CYP3A5 polymorphism can alter the pharmacokinetics and pharmacodynamics of some drugs, including anticancer agents and antihypertensive drugs.(8) Previous study has reported that the allelic frequencies of CYP3A5*2 (2480 G>A, 0.”
BackgroundRetractedParkhomenko, A. A., Застрожин, М. С., Скрябин, В. Ю., et al. (2023) · Психиатрия психотерапия и клиническая психология · doi:10.34883/pi.2023.14.4.009
Ivashchenko, D. V., Che, M. D., Aysin, F. R., et al. (2026) · Pharmaceuticals · doi:10.3390/ph19091401
“Investigating the effect of the CYP3A5*3 polymorphism on the efficacy and safety of other antipsychotics holds promise [32].”
Metadata
- Authors
- Ragia, G., Dahl, M.-L., & Manolopoulos, V.
- Affiliations
- Democritus University of Thrace (GR)
- Venue
- Current Drug Metabolism
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2016-02-12
- Volume
- 17
- Issue
- 3
- Pages
- 227-236
- ISSN
- 1389-2002 (ISSN-L)
- OpenAlex
- W2257506831
- Cited by
- 25
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 4
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Drug Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- CYP3A5, pharmacokinetics, antipsychotic drugs, antidepressants, carbamazepine, CYP3A4, drug metabolism, drug-drug interactions, first-pass metabolism, haloperidol, risperidone, quetiapine, aripiprazole, clozapine, olanzapine
- MeSH terms
- Anticonvulsants, Antidepressive Agents, Drug Interactions, Humans, Polymorphism, Genetic, Antipsychotic Agents, Cytochrome P-450 CYP3A
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