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Mammalian CYP2D Members A Comparison of Structure, Function, and Regulation
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Kerry et al. (1993) have compared the enzyme kinetics of dextromethorphan O- and N-demethylation and the N- and O-demethylation of the primary metabolites dextrorphan and 3-methoxymorphinan in liver microsomes from female DA and female SD rats. The intrinsic clearance (Vmax/Km) of the O-demethylation of 3-methoxymorphinan to 3-hydroxymorphinan is 180-fold lower in DA rats (0.11 vs. 20.77 ml/h/mg) because of a 60-fold higher Km (108.7 vs. 1.76 μM) and 3-fold lower Vmax (11.5 vs. 35.95 nmol/mg/h). The kinetics for dextrorphan N-demethylation to 3-hydroxymorphinan does not differ between the two strains. The Km for dextromethorphan N-demethylation to 3-methoxymorphinan is similar between SD and DA rats (85.04 vs. 68.99 μM). However, SD rats display a twofold higher Vmax (83.37 vs. 35.49 nmol/mg/h) and intrinsic clearance (0.96 vs. 0.51 ml/h/mg) than DA rats (Kerry et al. 1993). The O-demethylation of dextromethorphan to dextrorphan in SD rats shows a high- and low-affinity enzyme component, with the high-affinity intrinsic clearance contributing 98% of the total intrinsic clearance. Dextromethorphan O-demethylation in DA rats is characterized by a single enzyme system. The high-affinity O-demethylating enzyme in SD rats shows a 20-fold lower Km (2.5 vs. 55.6 μM) and a 3-fold higher Vmax (51.04 vs. 16.84 nmol/mg/h), resulting in a 66-fold higher intrinsic clearance (20.04 vs. 0.31 ml/h/mg) compared to DA rats (Kerry et al. 1993). Quinine, dextropropoxyphene, methadone, and propafenone inhibit 3-methoxymorphinan and dextromethorphan O-demethylation but do not inhibit dextrorphan or dextromethorphan N-demethylation at similar concentrations. These results demonstrate a clear strain difference in 3-methoxymorphinan O-demethylation and dextromethorphan O-demethylation between SD and DA rats, suggesting the key role of Cyp2d2 for these two reactions. In contrast, dextrorphan N-demethylation and dextromethorphan N-demethylation do not appear to be under genetic control in SD and DA rats, suggesting a minor role of Cyp2d2 for these reactions.
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
In PM, the area under the plasma concentration–time curve (AUC) and urinary recovery of 3-methoxymorphinan were increased, and a decrease of O-demethylation to 3-hydroxymorphinan via CYP2D6 was described (Nagai et al. 1996). On the other hand, in EM, there was almost nonexistent quantification of 3-methoxymorphinan due to the rapid conversion to 3-hydroxymorphinan catalyzed by CYP2D6. Still in the Japanese population, the ratios of the cumulative amounts of free and conjugated DXO to DXM excreted in the urine suffered extensive inter-subject variation, most probably related to the fact that the catalysis of DXM to DXO is mediated by CYP2D6; the ratios of DXO to 3-hydroxymorphinan were almost constant, as this reaction is CYP3A4 dependent. The percentages of conjugate metabolites to total metabolites (free and conjugated) were around 86.3–98.9% for both DXO and 3-hydroxymorphinan conjugates, in accordance with data from a French population. DXO and 3-hydroxymorphinan conjugative capacities were similar (mean of 95.7% and 96.7%, respectively), allowing to infer that this step might not be the rate limiting step in the DXM metabolic pathway (Nagai et al. 1996).
AVP-786 as a promising treatment option for Alzheimer’s Disease including agitation
Published in Expert Opinion on Pharmacotherapy, 2021
Rita Khoury, Charlotte Marx, Sidney Mirgati, Divya Velury, Binu Chakkamparambil, George T. Grossberg
DM also undergoes a minor metabolic pathway via CYP3A4/A5 and is N-demethylated into 3-methoxymorphinan [68]. Eventually, both DX and 3-methoxymorphinan are further demethylated to an inactive metabolite, 3-hydroxymorphinan [68].