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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Gepirone is a pyridinyl piperazine 5-HT1A agonist with antidepressant activity (McMillen and Mattiace 1983) used in the treatment of depression (Greenblatt et al. 2003). Gepirone undergoes extensive metabolism after oral administration, with the major metabolites in human plasma being 1-(2-pyrimidinyl)-piperazine and 3’-OH-gepirone (Figure 3.19) (von Moltke et al. 1998). CYP3A4 is the major enzyme for the formation of 1-(2-pyrimidinyl)-piperazine and accounts for 80%–90% of formation of hydroxylated metabolites at high substrate concentrations (≥10 μM). At low gepirone concentrations (≤1 μM), human liver microsomes form 1-(2-pyrimidinyl)-piperazine and 3’-OH-gepirone and two other hydroxylated metabolites (2-OH- and 5-OH-gepirone) (Greenblatt et al. 2003). All metabolites are formed by CYP3A4, but CYP2D6 forms 3’-OH- and 5-OH-gepirone, but not 1-(2-pyrimidinyl)-piperazine or 2-OH-gepirone (Greenblatt et al. 2003). On the basis of estimated relative abundances of the two CYPs in human liver, CYP3A4 is predicted to account for more than 95% of net clearance of gepirone in vivo at low concentrations approaching the therapeutic range, while CYP2D6 would account for less than 5% of net clearance.
New and Emerging Therapies for Anxiety
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
David J. Nutt, Spilios V. Argyropoulos
Gepirone is an analog of buspirone that is also a partial 5HT1A agonist. It has shown some efficacy in GAD [47] and panic disorder [44]. The trial by Rickels et al. included 198 patients with GAD and showed that the anxiolytic effect was delayed and more adverse effects were noted compared with diazepam. In contrast, rebound anxiety was not experienced upon ceasing gepirone, but it was seen in withdrawal from the benzodiaze-pine. Of interest is the fact that gepirone is also developed for atypical depression, a condition that is often associated with anxiety.
Pharmacological Treatment of Generalised Anxiety Disorder: Current Practice and Future Directions
Published in Expert Review of Neurotherapeutics, 2023
Harry A. Fagan, David S. Baldwin
Several additional 5-HT1A partial agonists are currently under development for the treatment of anxiety disorders. The azapirone gepirone was demonstrated to improve symptoms in patients with co-morbid GAD and panic disorder with agoraphobia in an open study [86]. However, no RCTs have been conducted to assess its efficacy in any anxiety disorder. In patients with MDD and a high level of anxiety symptoms, augmentation of SSRI treatment with azapirone tandospirone improved both depressive and anxiety symptoms [87]. A multicentre RCT conducted in China compared 60 mg vs. 30 mg/day of tandospirone in patients with GAD over 6 weeks [88]. However, the lack of a placebo group in this study makes overall interpretation of the efficacy of tandospirone challenging. The higher tandospirone dosage was associated with a greater HAM-A decrease but no difference in overall response rate. An additional 5-HT1A partial agonist with 5-HT2 antagonist actions (FKW00GA) is under development with reported efficacy in phase 2 trials in GAD [89]. To date, the results of these trials have not been published.