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Theoretical Biochemical Mechanisms for Drug Dependence
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
The mechanisms of the induction of microsomal drug-metabolizing enzymes (DMEs) in liver are not clearly understood. A proliferation of the liver endoplasmic reticulum is accompanied by an increase in protein synthesis6 and an increase in RNA synthesis,7 and by a decrease in RNA breakdown due to the progressive inhibition of RNAase activity during induction.8,9 The specificity in induction of the synthesis of the protein enzyme involved in the microsomal respiratory system is quite distinct from the general increase in protein synthesis induced by hepatec-tomy or by anabolic steriod hormones such as nortestosterone.10 In addition to the effect of the induction of the DMEs by inducer drugs, there is a direct competition between drugs for the DMEs in liver. In in vitro systems, many drugs can be shown to be competitive inhibitors for other drugs.11 In the intact animal, however, there are requirements of similarity of Km and Vmax values before one drug can have an important effect on the metabolism of another drug.12 Thus, ethylmorphine and codeine which have similar kinetic properties to hexobarbital inhibit hexobarbital metabolism in vivo while morphine and norcodeine do not.13
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Codeine as a prodrug (~10% of a dose) is metabolized by CYP2D6-mediated O-demethylation into its active form, morphine, which is the key metabolite responsible for the most antinociceptive effect of codeine, but most is glucuronidated to codeine-6-glucuronide and the remainder is metabolized by CYP3A4 to norcodeine (Figure 3.32) (Yue and Sawe 1997). Morphine is converted to its 3-O- and 6-O-glucuronide by UGT1A1, 1A8, and 2B7 (Coffman et al. 1997; King et al. 2000; Ohno et al. 2008). Morphine is N-demethylated to result in normorphine, which is then glucuronidated. Morphine-3-glucuronide, morphine-6-glucuronide, morphine-3,6-di-glucuronide, morphine 3-ethereal sulfate, normorphine, and normorphine 6-glucuronide are found in the urine of humans (Yeh et al. 1977), whereas codeine with a methoxy group on the 3-position is converted only to the 6-glucuronide.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Codeine is metabolised by O- and N-demethylation in the liver to morphine, norcodeine, and other metabolites including normorphine and hydrocodone. Metabolism to morphine is mediated by the cytochrome P450 isoenzyme CYP2D6, which shows genetic polymorphism. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.
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].
Detection of opioids in umbilical cord lysates: an antibody-based rapid screening approach
Published in Toxicology Mechanisms and Methods, 2019
Stuart J. Knight, Alexander D. Smith, Tricia E. Wright, Abby C. Collier
Pure codeine spiked into UC lysate approximated the commercial-spiked curve closely, with an LLOQ of 5.7 ng/ml (Figure 1C). However, absolute quantitation of opioids in UC lysate is not possible because several analytes have cross reactivity in excess of 100% in the commercial ELISA. In particular 6-acetylmorphine and 6-acetyl-codeine cross reactivity is 636% and 442% respectively, with thebaine (uncommonly seen in the real world) at 151%. Additionally, several other metabolites are detected at less than 100% cross-reactivity, including morphine 3βD glucuronide (46%), morphine 6βD glucuronide (35%), hydrocodone (22%), hydromorphone (20%), dihydrocodeine (15%), norcodeine (0.8%) and normorphine (0.6%), according to the manufacturer’s product literature. If testing occurred shortly (minutes to hours) after ingestion, results would initially be several fold higher than true as 6-acetyl morphine is produced quickly, but after this, results would be under predictive of ingestion as the poorly detected glucuronides become more abundant. Despite this, relative levels of quantification can be detected as ‘high’ or ‘low’, an improvement on the ‘yes’ or ‘no’ previously reported (Montgomery et al. 2006; Wright et al. 2011).