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Background: In vitro findings have indicated that the novel anxiolytic drug, deramciclane, is an inhibitor of the cytochrome P(450) (CYP) 2D6 enzyme and co-administration of deramciclane and the CYP2D6 probe drug desipramine is possible in clinical practice., Objective: To evaluate the effects of deramciclane on CYP2D6 activity as measured by desipramine pharmacokinetics and pharmacodynamics using paroxetine as a positive control for CYP2D6 inhibition., Methods: Fifteen healthy subjects received either 60 mg deramciclane, 20 mg paroxetine or matched placebo for 8 days in randomized order in this double-blind, cross-over study. On day 8 of each study phase, the subjects received a 100-mg single dose of desipramine. Desipramine and its CYP2D6-dependent metabolite, 2-OH-desipramine, concentrations were measured for 240 h. Measurement of secretion of saliva, Visual Analogue Scale assessment of dryness of mouth and tiredness were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane or paroxetine co-administration with desipramine., Results: Repeated administration of deramciclane doubled the AUC of desipramine ( P<0.001), while paroxetine caused a 4.8-fold increase in the AUC of desipramine ( P<0.001). Significant correlations were observed with paroxetine (r(s)=0.84, P<0.001) and deramciclane (r(s)=0.51, P=0.0498) concentrations and the magnitude of increase of desipramine AUC. Both deramciclane and paroxetine decreased the formation of 2-OH-desipramine in the first-pass phase. The AUC ratio of 2-OH-desipramine/desipramine was decreased by 39% ( P<0.001) by deramciclane and by 74% ( P<0.001) by paroxetine. There were no changes in the secretion of saliva during co-administration of desipramine with deramciclane compared with placebo., Conclusion: Although deramciclane seems to be a weaker inhibitor of CYP2D6 than paroxetine, dose adjustment of drugs metabolized by CYP2D6 may be needed when used concomitantly with deramciclane.

Rationale: Preliminary in vitro findings indicated that the novel anxiolytic drug, deramciclane is a substrate for the cytochrome P(450) (CYP) 3A4 isoenzyme. Moreover, its co-administration with buspirone, another anxiolytic drug, is likely in clinical practice., Objectives: The primary objective of the present study was to evaluate the in vivo effects of deramciclane on CYP3A4 activity as measured by buspirone pharmacokinetics. The secondary objective was to study the possible pharmacodynamic interaction between these two anxiolytic drugs., Methods: Sixteen healthy subjects received 60 mg deramciclane or matched placebo for 8 days in this randomized, double-blind, cross-over study. On day 8 of both phases, the subjects received a 20-mg single dose of buspirone. Buspirone and its active metabolite, 1-pyrimidylpiperazine (1-PP), concentrations were measured for 24 h. Pharmacodynamic testing and measurement of plasma prolactin concentrations were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane and buspirone co-administration., Results: Repeated administration of deramciclane had no effect on CYP3A4 activity as measured by buspirone pharmacokinetics. However, deramciclane administration caused an inhibition of the further, not CYP3A4-dependent, metabolism of 1-PP as evidenced by 84% increase in the AUC ( P<0.001) and 20% increase in the elimination half-life ( P=0.0012) of 1-PP. Deramciclane did not potentiate the buspirone-induced increase in prolactin secretion. No significant differences were found in the psychomotoric testing or the subjective maximum sedation between the deramciclane phase and the placebo phase, either before or after buspirone administration. Of 16 subjects, 5 experienced dizziness during both study phases., Conclusion: Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramciclane and a single dose of buspirone.

Objective: The aim of this study was to investigate the effect of hormone-replacement therapy (HRT) on the pharmacokinetics of the selective monoamine oxidase B inhibitor selegiline and its primary metabolites desmethylselegiline and l-metamphetamine., Methods: In this randomised, double-blind, cross-over trial, 12 healthy female subjects received once daily for 10 days either HRT containing 2 mg estradiol valerate and 250 microg levonorgestrel or matched placebo. On day 10, they took a single 10-mg oral dose of selegiline. The serum concentrations of selegiline, desmethylselegiline and metamphetamine were measured for 32 h., Results: There was a 59% difference ( P=0.14) in the area under the serum concentration-time curve (AUC) of selegiline during the HRT compared with the placebo phase, but only a little or no concomitant reduction in the AUC of desmethylselegiline (-7%, P=0.071) or metamphetamine (2%, P=0.614) was observed. Maximum plasma concentration (C(max)) of selegiline was not changed, but a small, statistically significant, reduction in the C(max) of desmethylselegiline (-17%, P=0.03) was seen during the HRT phase. The C(max) of methamphetamine was slightly but not significantly reduced (-5%, P=0.06). The unchanged AUC ratios of desmethylselegiline/selegiline and metamphetamine/selegiline indicate that the primary metabolism of selegiline was not affected by HRT. All study treatments were well tolerated., Conclusion: Unlike oral contraceptives, HRT is not likely to have clinically significant pharmacokinetic interaction with selegiline.

Objectives: To address the relevance of cytochrome P-450 (CYP) 2C19 polymorphism for the pharmacokinetics and dynamics of selegiline and its two known primary metabolites, desmethylselegiline and l-methamphetamine., Methods: Six extensive (mephenytoin S/R ratio < 0.3; EM) and six poor (mephenytoin S/R ratio > 0.8; PM) hydroxylators of S-mephenytoin ingested a single 10-mg oral dose of selegiline hydrochloride. Serum concentrations of selegiline, desmethylselegiline and l-methamphetamine were measured by gas chromatography--mass spectrometry for up to 48 h. In addition, the platelet monoamine oxidase type B (MAO-B) activity was measured for 14 days to describe possible differences in the pharmacodynamics of selegiline and its metabolites between EM and PM., Results: The CYP2C19 phenotype had no significant effects on the pharmacokinetic variables of selegiline. PM of S-mephenytoin had 68% higher mean AUC of desmethylselegiline (P = 0.0017) than EM, but no significant differences were observed in other pharmacokinetic parameters of desmethylselegiline. Contrary to desmethylselegiline, the serum l-methamphetamine concentrations were slightly lower in PM, but no statistically significant differences were observed in l-methamphetamine pharmacokinetics between the two CYP2C19 phenotypes. Accordingly, the magnitude of MAO-B inhibition showed no significant differences between the study groups., Conclusions: CYP2C19 polymorphism does not seem to be crucial for the metabolism or clinical effects of selegiline.

Objective: To characterise the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of selegiline in healthy volunteers., Methods: In this randomised, placebo-controlled crossover study with two phases, 12 healthy volunteers took either 200 mg itraconazole or matched placebo once daily for 4 days. On day 4, a single 10-mg oral dose of selegiline hydrochloride was administered. Serum concentrations of selegiline and its primary metabolites desmethylselegiline and l-methamphetamine were determined up to 32 h. A caffeine test was performed on day 3 of both phases, by measuring the plasma paraxanthine/caffeine concentration ratio 6 h after caffeine intake, to examine the role of CYP1A2 in selegiline pharmacokinetics. In addition, the effects of itraconazole on the metabolism of selegiline in vitro were characterised by using human liver microsomes., Results: Itraconazole had no significant effects on the pharmacokinetic variables of selegiline, desmethylselegiline or l-methamphetamine, with the exception that the AUC of desmethylselegiline was increased by about 10% (P < 0.05). There was a significant correlation between the AUC(desmethylselegiline)/AUC(selegiline) ratio and the paraxanthine/caffeine ratio (r = 0.41; P < 0.05), suggesting involvement of CYP1A2 in the formation of desmethylselegiline. In experiments with human liver microsomes, itraconazole had no inhibitory effect on the formation of either desmethylselegiline or l-methamphetamine from selegiline., Conclusions: The pharmacokinetics of selegiline in healthy volunteers were unaffected by the potent CYP3A4 inhibitor itraconazole. In addition, itraconazole showed no inhibitory effect on the biotransformation of selegiline to desmethylselegiline and l-methamphetamine by human liver microsomes. These findings suggest that selegiline is not susceptible to interaction with CYP3A4 inhibitors.