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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Hydrocodone is a semisynthetic opioid analog used to treat moderate pain and as an antitussive. Hydrocodone differs structurally from codeine in that the C6-position is occupied by a keto group, and thus it does not undergo the extensive conjugation (>60%) that codeine undergoes. The therapeutic range of hydrocodone is 1–30 ng/ml and the toxic plasma concentration is >100 ng/ml. Approximately 26% of a single dose is excreted in a 72-h urine collection that consists of unchanged drug (~12%), norhydrocodone (5%), conjugated hydrocodone (4%), 6-hydrocodol (3%), and conjugated 6-hydromorphol (0.1%) (Barakat et al. 2014). Approximately 40% of the clearance of hydrocodone is via non-CYP pathways. The metabolism of hydrocodone is similar to codeine, resulting in the major active metabolite hydromorphone (Figure 3.34). The μ opioid receptor binding affinity of hydromorphone is 10- to 33-fold greater than that of hydrocodone (Chen et al. 1991). Hydrocodone is metabolized by O- and N-demethylation, resulting in hydromorphone and norhydrocodone, respectively, and reduction of the 6-keto group. C6-keto reduction results in approximately equal amounts of 6-α-hydrocol and 6-β-hydrocol. The O-demethylation of hydrocodone is predominantly catalyzed by CYP2D6 and, to a lesser extent, by an unknown low-affinity CYP (Hutchinson et al. 2004). Norhydrocodone formation is mediated by CYP3A4.
The North American opioid epidemic: opportunities and challenges for clinical laboratories
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Sarah R. Delaney, Danyel H. Tacker, Christine L. H. Snozek
While cross-reactivity with non-class drugs and other compounds is less common in MS than in IA methods, such interferences can complicate analysis (Figure 2, right). Isobaric compounds (i.e. drugs that share the same mass or m/z) can confound interpretation if they are not adequately separated by either chromatography or fragmentation. The opioid drug class is especially challenging, as many parent drugs and metabolites share the same mass. Examples of isobaric opioids include morphine, hydromorphone, norcodeine (codeine metabolite), and norhydrocodone (hydrocodone metabolite), which all share the m/z of 286.1 g/mol. Non-opioids can also cause isobaric interference; e.g. tramadol (a synthetic opioid) and the desmethyl metabolite of venlafaxine (an antidepressant) both share the mass of 277.403 g/mol [49]. Given the rapid evolution of FAs and other synthetic opioids, laboratories must be aware that even well-validated MS assays can misidentify novel compounds due to structural similarity with previously-characterized opioids [52].
An update on the safety of prescribing opioids in pediatrics
Published in Expert Opinion on Drug Safety, 2019
Jagroop M. Parikh, Patricia Amolenda, Joseph Rutledge, Alexandra Szabova, Vidya Chidambaran
Hydrocodone is 12 times more potent at the opioid receptor than codeine [85] and is metabolized by CYP2D6 and CYP3A4 into an active metabolite hydromorphone and norhydrocodone, respectively. CYP2D6 UM may thus have up to an eightfold greater plasma concentration of hydromorphone, whereas PM receives minimal analgesia [86]. In response to the occurrence of >400 cases of adverse events associated with its use between 1969 and 2005, the US FDA has banned the sale of more than 200 hydrocodone products, as it is a common component of antitussive medications [87].