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Licit and illicit drugs
Published in Jason Payne-James, Richard Jones, Simpson's Forensic Medicine, 2019
Jason Payne-James, Richard Jones
Five drugs fall into this category: phencyclidine (PCP), ketamine, γ-hydroxybutyrate (GHB), dextro-methorphan and Salvia divinorum (Figure 24.17). All are hallucinogens, and the first four share the same mechanism of action: they block the NMDA receptor, the predominant molecular mechanism involved in memory function and learning. Salvia has no effect on the NMDA channel. Instead, it specifically blocks the κ receptor. Drugs that bind to the κ receptor usually produce intense feelings of unhappiness and depression and all have hallucinogenic (psychotomimetic) effects.
Inhibitors of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Lansoprazole is more potent (Ki = 44.7 μM) than omeprazole (Ki = 240.7 μM) as an inhibitor of CYP2D6-mediated conversion of dextromethorphan to dextrorphan (Figure 4.12) (Ko et al. 1997). Mexiletine competitively inhibits dextro-methorphan O-demethylation in human liver microsomes, and propafenone, oxprenolol, propranolol, and ajmaline inhibit the CYP2D6-mediated formation of hydroxymethylmexiletine and p-hydroxymexiletine from mexiletine (Figure 4.12) (Broly et al. 1990). Omeprazole inhibits CYP2D6-dependent 1′-hydroxylation of bufuralol with a Ki of 302 μM (VandenBranden et al. 1996). Several clinical studies have shown that omeprazole has no clinically important inhibitory effect on the clearance of drugs such as metoprolol (Andersson et al. 1991) and propranolol (Henry et al. 1987), which are partially metabolized by CYP2D6. Omeprazole seems to be a particularly selective inhibitor of CYP2C19, and it has a weak interaction with CYP2D6.
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
DXM (3-methoxy-N-methylmorphinan; Figure 1) is the dextrorotatory [d- or (–)] enantiomer of levomethorphan [l- or (+)], which is the methyl ether of DXO (3-hydroxy-N-methylmorphinan) and levorphanol, respectively (Sromek et al. 2014). Although former levorotatory compounds are both opioid analgesics, only levorphanol was clinically developed (Gudin et al. 2016; Le Rouzic et al. 2019). Moreover, levorphanol is the levorotatory isomer of racemic 3-hydroxy-N-methylmorphinan (Dromoran®) and named as Levo-Dromoran®. DXM is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. It is also the d-isomer of methorphan (racemic mixture), but unlike the l-isomer, it does not have opioid activity. Methorphan presents as two isomeric forms, each with differing pharmacology and effects with respect to its two enantiomers. The DXM is used as an antitussive drug in cough medicines (and in high doses, it is a dissociative hallucinogen), whereas the levorotatory enantiomer levomethorphan, a prodrug of levorphanol, is a strong opioid analgesic that is listed as a schedule II drug in the USA (Wong and Sunshine 1996; Bortolotti et al. 2013; Gudin et al. 2016). Levorphanol binding affinity for the mu (MOR; µ) opioid receptor, 0.42 nM, is greater than the affinity of morphine, 1.24 nM and also presents longer t1/2 (Bortolotti et al. 2013). As DXM is approved for use in OTC drugs, accurate control of enantiomeric purity is essential to assure that commercial DXM preparations do not contain the l-enantiomer.