CYP450-based reclassification of urinary metabolic ratio cutoffs for pain management and substance abuse treatment drugs.

Authors

Amadeo J Pesce, Agnes Cua, Eugene Wickett

Published in

Journal of opioid management. Volume 21. Issue 7. Pages 96-113.

Abstract

Traditional 95 percent reference intervals (RIs) for urinary metabolic ratios (MRs) are useful for identifying unusually slow or fast metabolism, but these do not account for cytochrome P450 (CYP450)-mediated variability in drug metabolism. In this study, we re-evaluated MR cutoff limits for 18 metabolite-parent drug pairs using genotype-predicted phenotype frequencies reported by Zhu et al. These pairs include dextrorphan/dextromethorphan, oxymorphone/oxycodone, hydromorphone/hydrocodone, O-desmethyltramadol/tramadol, hydromorphone/-morphine, norbuprenorphine/buprenorphine, norfentanyl/-fentanyl, -noroxycodone/-oxycodone, norhydrocodone/hydrocodone, -7-aminoclonazepam/clonazepam, α-hydroxyalprazolam/alprazolam, norquetiapine/quetiapine, meprobamate/carisoprodol, N-desmethyltapentadol/tapentadol, norketamine/ketamine, -2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine/methadone, -desipramine/imipramine, and nortriptyline/amitriptyline. Using a dataset of 2.2 million urine drug testing (UDT) specimens collected from pain management and rehabilitation clinics, we calculated new MR cutoffs that reflect CYP phenotype distributions. CYP2D6-metabolized drug pairs showed consistent upward shifts in both lower and upper limits relative to 95 percent RIs; for example, the -dextrorphan/dextromethorphan lower limit increased from 0.157 to 0.277 and the upper limit from 245.140 to 282.448. CYP2C19-metabolized pairs demonstrated minimal changes to lower limits but marked decreases in upper limits, eg, meprobamate/carisoprodol upper limit decreased from 942.04 to 133.44, consistent with the high prevalence of increased-function alleles. For CYP3A4, CYP2C9, and CYP2B6, only lower thresholds could be derived, reflecting the absence of validated ultrarapid metabolizer categories. Across drug pairs, CYP-specific thresholds reclassified 2.99-27.86 percent of specimens that fell outside the CYP-informed limits. MR-derived phenotype classifications aligned with the phenotype frequencies reported in Zhu et al., indicating that population-level MR distributions reflect known CYP450 genetic variability. Incorporating CYP-specific cutoffs alongside traditional 95 percent RIs may improve identification of expected genetic metabolism, reduce misclassification, and enhance the interpretive accuracy of MR analysis in clinical UDT.

PMID:
42429026
Bibliographic data and abstract were imported from PubMed on 10 Jul 2026.

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