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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.
Effect of laparoscopic sleeve gastrectomy on drug pharmacokinetics
Published in Expert Review of Clinical Pharmacology, 2021
Kaifeng Chen, Yaqi Lin, Ping Luo, Nan Yang, Guoping Yang, Liyong Zhu, Qi Pei
Dextrorphan is the O-demethylated metabolite of dextromethorphan, which can be further N-demethylated to form 3-hydroxymorphinan (morphinan-3-ol) by CYP3A4 [32]. The effect of body mass index and bariatric surgery (LSG and RYGB) on CYP3A4 activity was investigated both prior to surgery and at 1 month and 6 months after surgery [17]. CYP3A4 activity was markedly lower in patients with extreme obesity than in normal-weight controls. This could be explained by the fact that the dextrorphan/3-hydroxymorphinan ratio (CYP3A4-mediated substrate/product ratio) had a positive correlation with BMI. Interestingly, bariatric surgery normalized CYP3A4 activity. Although such effects were observed in both surgical types, they occurred earlier in LSG (with statistical significance achieved at 4 weeks post-operation and maintained at 6 months) as opposed to RYGB (for which statistical significance was noted at 6 months after surgery).
Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects
Published in Drug Metabolism Reviews, 2020
Ana Rita Silva, Ricardo Jorge Dinis-Oliveira
The metabolic pathways of DXM are shown in Figure 2. DXM is primarily rapid and extensively O-demethylated by CYP2D6 to DXO, its major active metabolite (Nagai et al. 1996; Zhou and Meibohm 2013). Nevertheless, the therapeutic activity is believed to be caused by both DXM and DXO (Braga et al. 1994). Indeed, in vitro studies showed that DXM was a more potent NMDA antagonist than DXO (Szekely et al. 1991; Dematteis et al. 1998; Nicholson et al. 1999). Additionaly, experimental and clinical evidence suggests that the antinociceptive, neuromodulatory and neuroprotective in vivo effects of DXM result mainly from a central action of unchanged DXM rather than from its more active metabolite DXO (Steinberg et al. 1993; Desmeules et al. 1999). This metabolic reaction can also be, at lower extent, catalyzed by CYP2C9 and CYP3A4/5 (Takashima et al. 2005). CYP3A4 and CYP3A5 are the major enzymes (with certain contribution from CYP2D6) implicated in the N-demethylation of DXM to 3-methoxymorphinan and DXO to 3-hydroxymorphinan (Jacqz-Aigrain et al. 1993; Yu and Haining 2001; Takashima et al. 2005). 3-Methoxymorphinan undergoes further O-demethylation mediated by CYP2D6 to 3-hydroxymorphinan (Strauch et al. 2009). Subsequently, DXO and 3-hydroximorphinan are subjected to glucuronide and sulfate conjugation and then excreted (Nagai et al. 1996). In fact, the major urinary excretion products are the glucuronide conjugates of DXO and 3-hydroxymorphinan, dextrorphan-O-glucuronide and 3-hydroxymorphinan-O-glucuronide (Strauch et al. 2009).
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].