Artigo de revisão
Influence of cytochrome P450 polymorphisms on toxicokinetics and the toxicological interpretation of drugs and forensic substances: an integrative review
Como citar: Albuquerque I. Influence of cytochrome P450 polymorphisms on toxicokinetics and the toxicological interpretation of drugs and forensic substances: an integrative review. Persp Med Legal Pericia Med. Vol. 11, 2026; 260957.
https://dx.doi.org/10.47005/260957
Recebido em 09/08/2026
Aceito em 29/09/2026
The authors report no conflict of interest.
Influence of cytochrome P450 polymorphisms on toxicokinetics and the toxicological interpretation of drugs and forensic substances: an integrative review
Resumo
INTRODUÇÃO: A resposta aos xenobióticos pode variar significativamente entre os indivíduos em razão de fatores genéticos, fisiológicos e ambientais, destacando-se os polimorfismos das enzimas do citocromo P450 (CYP450). MATERIAL E MÉTODO: Esta revisão integrativa analisou a influência de polimorfismos das isoenzimas CYP2D6, CYP2C19, CYP2C9 e CYP3A4/5 na toxicocinética e interpretação toxicológica forense, por meio de busca nas bases PubMed e Web of Science até setembro de 2025, resultando na inclusão de 15 estudos. RESULTADOS: As pesquisas indicam que variações na atividade das enzimas CYP modificam a depuração e a exposição sistêmica. Na toxicologia forense, estudos com venlafaxina, tramadol, oxicodona e $Delta^9$-THC demonstram que dados genéticos auxiliam na interpretação de concentrações atípicas, embora a genotipagem post-mortem não deva ser isolada de achados circunstanciais e necroscópicos. DISCUSSÃO: A associação entre farmacogenética, razões metabólicas e análise quiral amplia a compreensão de casos complexos, apesar da necessidade de maior padronização metodológica. CONCLUSÃO: A genotipagem post-mortem consolida-se como ferramenta complementar de grande valia para cenários toxicológicos complexos, exigindo correlação multidisciplinar.
Palavras Chave: Farmacogenômica; Citocromo P450; Toxicologia Forense; Polimorfismo Genético; Metabolismo de Fármacos
Abstract
INTRODUCTION: The response to xenobiotics may vary considerably due to genetic factors, notably polymorphisms in cytochrome P450 (CYP450) drug-metabolizing enzymes. MATERIAL AND METHOD: This integrative review analyzed the influence of CYP2D6, CYP2C19, CYP2C9, and CYP3A4/5 polymorphisms on toxicokinetics and forensic interpretation, through a structured search in PubMed and Web of Science up to September 2025, yielding 15 studies. RESULTS: Variations in CYP activity alter drug clearance and systemic exposure. In forensic contexts, studies involving venlafaxine, tramadol, oxycodone, and $Delta^9$-THC show that genetic insights assist in interpreting atypical concentrations, though post-mortem genotyping must not be used in isolation. DISCUSSION: Combining pharmacogenetics, metabolic ratios, and chiral analysis enhances the understanding of complex cases, highlighting the need for methodological standardization. CONCLUSION: Post-mortem genotyping serves as a valuable complementary tool for complex toxicological scenarios when correlated with multidisciplinary findings.
Keywords (MeSH): Pharmacogenomics; Cytochrome P450; Forensic Toxicology; Genetic Polymorphism; Drug Metabolism
References
1. Di Nunno N, et al. Pharmacogenetics and forensic toxicology: a new step towards a multidisciplinary approach. Toxics. 2021;9(11):292.
2. Zhao M, et al. Cytochrome P450 enzymes and drug metabolism in humans. Int J Mol Sci. 2021;22(23):12808.
3. Musshoff F, Stamer UM, Madea B. Pharmacogenetics and forensic toxicology. Forensic Sci Int. 2010;203(1-3):53-62.
4. Jakobsson G, et al. Oxycodone findings and CYP2D6 function in postmortem cases. Forensic Sci Int Genet. 2021;53:102510.
5. Kingbäck M, et al. Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood. Forensic Sci Int. 2012;214(1-3):124-34.
6. Aly SM, et al. Metabolic ratios and SNPs implicated in tramadol-related deaths. Int J Legal Med. 2023;137(5):1415-28.
7. Petrovitch D, et al. Scoping review of associations between cytochrome P450 3A4/5 single nucleotide polymorphisms and risk factors for fentanyl overdose. Pharmacogenomics. 2025;26(10-12):391-425.
8. Gasse A, et al. Toxicogenetic analysis of $Delta^9$-THC-metabolizing enzymes. Int J Legal Med. 2020;134(6):2095-103.
9. Wohlfarth A, et al. Looking at flubromazolam metabolism from four different angles: metabolite profiling in human liver microsomes, human hepatocytes, mice and authentic human urine samples with liquid chromatography high-resolution mass spectrometry. Forensic Sci Int. 2017;274:55-63.
10. Bickel J, et al. Post-mortem chiral analysis of MDMA and MDA in human blood and hair. Forensic Sci Int. 2024;364:112226.
11. Jornil J, et al. A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine. Forensic Sci Int. 2013;226(1-3):e26-31.
12. Whitledge JD, Watson CJ, Burns MM. Chronic Doxepin Toxicity Masquerading as Epilepsy in a 10-Year-Old Boy. J Med Toxicol. 2023;19(4):405-10.
13. Becquemont L. Type 1 Gaucher disease (CYP2D6-eliglustat). Thérapie. 2017;72(2):323-6.
14. Zhang Y, et al. CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms. PeerJ. 2024;12:e18636.
15. The Association of CYP2D64 and POR28 Polymorphisms on Mirtazapine Plasma Level in Subjects with Major Depressive Disorder and Anxiety Disorders. Comb Chem High Throughput Screen. 2020;23(10):1032-40.
