{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T12:47:59Z","timestamp":1782996479907,"version":"3.54.5"},"reference-count":62,"publisher":"Weston Medical Publishing","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Opioid Management"],"abstract":"<jats:p>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\u2013parent 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, \u03b1-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.<\/jats:p>","DOI":"10.5055\/jom.1001","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T12:19:35Z","timestamp":1782994775000},"page":"96-113","source":"Crossref","is-referenced-by-count":0,"title":["CYP450-based reclassification of urinary metabolic ratio cutoffs for pain management and substance abuse treatment drugs"],"prefix":"10.5055","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3748-9703","authenticated-orcid":false,"given":"Amadeo J.","family":"Pesce","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Cua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Wickett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"3008","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"102542","doi-asserted-by":"crossref","unstructured":"Zhu GD, Whitley P, LaRue L, et al.: Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests. 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