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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Bicifadine, a nonnarcotic analgesic that inhibits norepinephrine and serotonin uptake (Epstein et al. 1982), is used in the treatment of acute dental pain and postoperative bunionectomy pain (Wang et al. 1982). It is hydroxylated at its methyl group to form M2, by CYP2D6 with lesser contribution from CYP1A2 (Figure 3.49) (Erickson et al. 2007). In recombinant enzymes, CYP2D6 has a sixfold greater activity than that of 1A2. M2 is oxidized further to the carboxylic acid metabolite (M3). Bicifadine also underwent NADPH-independent oxidation at the C2-position of the pyrrolidine ring, generating a lactam metabolite (M12), which is catalyzed by MAO-B (major) and MAO-A (Erickson et al. 2007). M12 is further oxidized to a hydroxymethyl metabolite (M8) by CYP1A2, 2C19, 2D6, and 2E1. M8 is also further oxidized to a carboxyl metabolite M9, and both M8 and M9 could be glucuronidated. Alternatively, bicifadine is metabolized to the carbamyl-O-glucuronide (M11). In healthy subjects receiving a single dose (200 mg), approximately 64% of the dose is metabolized to the lactam acid (M9) and its acyl glucuronide; another 23% is recovered as M3 and its acyl glucuronide (Krieter et al. 2008). Neither bicifadine nor M12 is detected in human urine or feces.
Triple reuptake inhibitors (TRIs): do they promise us a rose garden?
Published in Psychiatry and Clinical Psychopharmacology, 2018
Like other classes of antidepressant medications, TRIs hold promise for a variety of other therapeutic indications. One emerging area of research indicates the potential antinociceptive effects of triple inhibitors, which is expected given the numerous data supporting the utility of TCAs and SNRIs for pain syndromes. Preclinical research with bicifadine demonstrated its antinociceptive effects in animal models of acute, persistent, and chronic pain syndromes. These effects were reduced in some experimental conditions by the co-administration of sulphide (a dopamine-2 receptor antagonist), suggesting that enhancement of dopamine neurotransmission is important for the full antinociceptive effect of bicifadine [17]. In a phase IIa pilot study in Alzheimer’s disease, tesofensine treatment was associated with cognitive improvements [18, 19]; although it has been proposed that tesofensine indirectly stimulates cholinergic neurotransmission, the physiological mechanism of this observation remains to be unclear. Weight loss has been observed as an adverse event in studies of tesofensine [20], prompting further research for the indication of obesity. One published preclinical study describes the effect of the balanced triple reuptake inhibitor DOV 102,677 in reducing volitional alcohol consumption in ethanol-preferring rats without decreasing food or water consumption [21]. However, it should be noted that monoamine reuptake inhibitors have historically performed better in animal models of addiction than in human clinical trials. However, it is possible that agents which inhibit dopamine reuptake might offer improved efficacy in substance use disorders due to the link between dopamine and reward-circuitry related behaviours.