Gerlach Samuel, Maruf Abdullah Al, Shaheen Sarker M, McCloud Ryden, Heintz Madison, McAusland Laina, Arnold Paul D, Bousman Chad A
Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Clin Pharmacol Ther. 2025 Mar;117(3):670-675. doi: 10.1002/cpt.3534. Epub 2024 Dec 17.
Pharmacogenetics-predicted drug metabolism may not match clinically observed metabolism due to a phenomenon known as phenoconversion. Phenoconversion can occur when an inhibitor or inducer of a drug-metabolizing enzyme is present. Although estimates of phenoconversion in adult populations are available, prevalence estimates in youth populations are limited. To address this gap, we estimated the prevalence of phenoconversion in 1281 youth (6-24 years) receiving pharmacotherapy for mental health conditions and who had pharmacogenetics testing completed for four genes (CYP2B6, CYP2C19, CYP2D6, CYP3A4). Self-reported medication and cannabidiol/cannabis use were collected at the time of pharmacogenetics testing. Nearly, half (46%) of the cohort was estimated to be phenoconverted for one of the four genes examined. Comparison of metabolizer phenotype frequencies before and after adjustment for phenoconversion showed significantly more youth had actionable phenotypes for CYP2C19 (60.3% vs. 69.1%; P =< 0.001), CYP2D6 (49.3% vs. 63.0%; P =< 0.001), and CYP3A4 (8.5% vs.12.2%; P = 0.003) after phenoconversion adjustment. Of youth who were phenoconverted, 24% had a change in their metabolizer phenotype that would lead to current pharmacogenetics-based prescribing guidelines recommending a change to standard prescribing (dose adjustment, alternative medication). Our findings indicate a high prevalence of cytochrome P450 phenoconversion among youth receiving pharmacotherapy for mental health conditions. Adjustment for phenoconversion should be considered when implementing pharmacogenetics testing in youth populations to improve the clinical utility of this testing in practice.
由于一种称为表型转换的现象，药物遗传学预测的药物代谢可能与临床观察到的代谢不匹配。当存在药物代谢酶的抑制剂或诱导剂时，就会发生表型转换。虽然已有成人人群表型转换的估计数据，但青少年人群中的患病率估计有限。为了填补这一空白，我们估计了1281名接受心理健康药物治疗且已完成四个基因（CYP2B6、CYP2C19、CYP2D6、CYP3A4）药物遗传学检测的青少年（6 - 24岁）中表型转换的患病率。在进行药物遗传学检测时收集了自我报告的用药情况以及大麻二酚/大麻使用情况。估计该队列中近一半（46%）的人在检测的四个基因之一上发生了表型转换。对表型转换进行调整前后代谢者表型频率的比较显示，在调整表型转换后，CYP2C19（60.3%对69.1%；P <= 0.001）、CYP2D6（49.3%对63.0%；P <= 0.001）和CYP3A4（8.5%对12.2%；P = 0.003）有可采取行动表型的青少年明显增多。在发生表型转换的青少年中，24%的人代谢者表型发生了变化，这将导致目前基于药物遗传学的处方指南建议改变标准处方（剂量调整、更换药物）。我们的研究结果表明，在接受心理健康药物治疗的青少年中，细胞色素P450表型转换的患病率很高。在青少年人群中实施药物遗传学检测时应考虑对表型转换进行调整，以提高该检测在实际临床中的应用价值。
