Discussion The main findings from our pharmacokinetic study on the S-ketamine oral thin film are summarized as follows: (i) the oral thin film was safe and the participants experienced mild adverse events infrequently related to the application of the film; (ii) S-ketamine bioavailability from the OTF was on average 26%; (iii) a 20% lower bioavailability of the 100 mg OTF relative to the 50 mg OTF was observed although this difference did not reach the level of significance; (iv) due to the large first pass-effect, 80% of S-ketamine was metabolized into S-norketamine leading to high concentrations of Snorketamine following sublingual or buccal film application for at least 6 h; (v) 56% of S-ketamine was finally metabolized into S-hydroxynorketamine, similarly, giving high plasma concentration for at least 6-hours; (vi) no differences in pharmacokinetics were observed for the sublingual or buccal administration routes; (vii) pharmacokinetic parameter estimates are in agreement with earlier findings. The OTF is rapidly, that is within 2 min, dissolved in saliva. Subjects were not allowed to swallow for 10 min after the oral film was applied, and retained the dissolved S-ketamine in their mouth. The process of local absorption took on average 13 min (Table 2.4), indicative that some Sketamine remained on the mucosa after swallowing. The majority of the Sketamine was swallowed after 10 min, and moved into the gastrointestinal tract, where it was absorbed and transported via the portal vein to the liver, where further biotransformation occurred. We remain uninformed regarding the 20% loss of S-ketamine.2 This may be related to loss in the gut, or metabolism into other metabolites than S-norketamine. It is thought that about 10% of ketamine is eliminated unchanged in the gut. A minor metabolic pathway is the hydroxylation of S-ketamine into 4-hydroxyketamine and some other metabolites (e.g. hydroxyhpenylketamine).12 The majority of S-ketamine (80%) undergoes hepatic N-demethylation into S-norketamine by cytochrome P450 (CYP) enzymes 2B6 and 3A4.12,13 We cannot exclude that some part of the S-ketamine is metabolized in extrahepatic tissues, such as oral or gut mucosal cells.14,15,16 This possibility is represented in the pharmacokinetic model (Figure 2.2) by the dotted red lines, which symbolize metabolic pathways of the oral and gut mucosa. Cytochrome P450 enzymes such as CYPA34 but not CYP2D6 are expressed in the oral mucosal lining.15 Similarly, the intestinal mucosa contains CYP3A4 and may possibly be an important route for first-pass conversion of S-ketamine and production of S-norketamine.15 However, previous studies showed just a minor role for gut wall clearance in the overall metabolism of S-ketamine with a ratio of intestinal mucosal clearance to hepatic clearance of 1:253.17 Because of this reason and the fact that we cannot discriminate between first-pass hepatic clearance and gut wall clearance, we modeled the S-ketamine first-pass effect through parenchymal liver metabolism 32
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