Marked effect of liver and kidney function on the pharmacokinetics of selegiline.

OBJECTIVES: The pharmacokinetics of selegiline was investigated in an open study with 4 parallel groups of 10 subjects in each. Patients with liver disease, those receiving a drug that induced hepatic enzyme activity, and those with impaired kidney function were compared with control subjects. METHODS: A single oral 20-mg dose of selegiline was administered after an overnight fast, and blood samples were collected over a period of 48 hours. Concentrations of serum selegiline and its main metabolites were determined and pharmacokinetic parameters calculated. RESULTS: The pharmacokinetic parameters of selegiline differed considerably between the patient groups and the control subjects. The area under the concentration-time curve of serum selegiline was, on average, 18-fold higher (P < .05) in patients with impaired liver function, 23-fold lower (P < .001) in patients with drug-induced liver function, and 6-fold higher (P < .05) in patients with impaired kidney function as compared with the control subjects. There was a large interindividual variation in every group. The changes in selegiline metabolite kinetics supported the changes in the kinetics of the parent compound. CONCLUSION: The elimination rate of selegiline was substantially increased in patients with drug-induced liver function and decreased in patients with impaired liver or kidney function when compared with control subjects. These results suggest that selegiline dosage adjustments may be required in patients with altered liver and kidney function.

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.

Cardiovascular and parasympathetic effects of dexmedetomidine in healthy subjects.

We evaluated the cardiovascular effects of intravenously (i.v.) and buccally administered dexmedetomidine, a selective alpha2-adrenoceptor agonist. Six healthy male subjects were studied unmedicated and after 2 micro g/kg i.v. or buccal doses of dexmedetomidine, using repeated recordings of ECG and blood pressure. Cardiac parasympathetic activity was estimated by measurements of high-frequency (HF) heart rate variability. Intravenous, but not buccal, dexmedetomidine raised systolic blood pressure by 11 +/- 5 mmHg (mean +/- SEM) and diastolic by 16 +/- 3 mmHg (maxima at 10 min). Later on, both i.v., and buccal dexmedetomidine produced a very similar hypotensive effect: on average, >or=10 mmHg reductions in systolic and diastolic pressure at 3 h. Intravenous dosing was followed by a decline in heart rate (-11 +/- 2 beats/min) accompanied by a trend toward enhanced HF variability (maximal effect at 10 min), which probably reflected baroreflex-mediated parasympathetic efferent neuronal activation. Buccal dexmedetomidine increased significantly the HF variability (maximum at 45 min) without influencing heart rate. We conclude that dexmedetomidine, when administered by a method that avoids concentration peaks, e.g., buccal dosing, can be used to produce a prolonged augmentation of cardiac parasympathetic efferent neuronal activity.

Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics.

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.

Bioavailability of dexmedetomidine after extravascular doses in healthy subjects.

AIM: To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2-adrenoceptor agonist, in healthy subjects. METHODS: Single 2 microg x kg-1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration-time data were analysed using linear one-compartment (buccal and peroral data), or two-compartment modelling (intravenous data), or noncompartmental methods (intramuscular data). RESULTS: Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12-20%), 82% (73-92%) and 104% (96-112%), respectively. CONCLUSION: Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug.

Pharmacokinetics of deramciclane, a novel anxiolytic agent, after intravenous and oral administration.

BACKGROUND AND OBJECTIVE: Deramciclane is a new compound that has shown anxiolytic effects in animal experiments and in human studies. The aim of this study was to determine the pharmacokinetic parameters of deramciclane after intravenous and oral administration, and its oral bioavailability. METHODS: Deramciclane 30 mg was given intravenously and orally as a tablet and as solution in an open, randomised, crossover three-period trial to 12 healthy male volunteers. Oral bioavailability of deramciclane and the pharmacokinetic parameters of deramciclane and N-desmethylderamciclane, the principal metabolite, were determined after intravenous and oral administration of the parent drug. RESULTS: The first and second distribution half-lives (mean +/- SD) of deramciclane were 0.04 +/- 0.01 and 3.03 +/- 0.50h, respectively, and the half-life of the elimination phase was 26.6 +/- 5.5h. The clearance of deramciclane after an intravenous dose was 0.24 +/- 0.10 L/kg. The elimination phase half-life of N-desmethylderamciclane was 38.2 +/- 6.9h after intravenous and about 25 h after oral dosing of the parent compound. The mean oral bioavailability of deramciclane was 44% (range 27-58%) and 36% (23-50%) after administration of the oral solution and tablet, respectively. Deramciclane was well tolerated even after a 30 mg intravenous dose resulting in peak plasma concentrations 10 times higher than observed after its oral administration. CONCLUSIONS: After intravenous administration, the pharmacokinetics of deramciclane are adequately described by a three-compartment model. After oral administration its pharmacokinetics follow a two-compartment model with first-order absorption. The elimination phase half-life of the parent compound is similar after intravenous and oral administration, whereas the apparent half-life of N-desmethylderamciclane is longer after intravenous than after oral administration of the parent compound. The oral bioavailability of deramciclane is large and uniform enough to allow its clinical use as tablets.

Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone.

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.

Effect of concomitant hormone replacement therapy containing estradiol and levonorgestrel on the pharmacokinetics of selegiline.

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.