The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD) were evaluated in twelve healthy non-smokers (NS) and twelve smokers (S, ? 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained-release tablets in an open-label, parallel-group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8±25.8 versus 48.2±14.01 h^?1) or peak adinazolam plasma concentrations (C_max) (93.3±31.8 versus 90.4±18.0 ng ml^?1) between groups. NDMAD AUC (2541.457 versus 2798±447 ng h ml^?1) and C_max (173±30.3 versus 175±26.9 ng ml^?1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non-smokers (8.7±0.7 versus 10.7±2.71 h^?1; p<0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol-digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.     

Comparison of alprazolam plasma levels in normal Asian and Caucasian male volunteers

Single-dose pharmacokinetics of alprazolam was studied in 42 normal male volunteers (14 Caucasians, 14 American-born Asians, and 14 foreign-born Asians), after both oral and parenteral (IV) administration of a small dose (0.5 mg) of the test drug. Asians manifested significantly higher C _max, larger AUC, slower CL and longer t 1/2 under both testing situations. When body surface area was used as a covariate, these cross-ethnic differences remained statistically significant (except C _max) after oral but not IV drug administration. There were no differences between the two Asian groups in any of these parameters examined in this study. These results confirmed previous observations of ethnic differences in the pharmacokinetic response between Asians and Caucasians and suggested that smaller doses of alprazolam may be required for Asians for similar clinical effects as compared to their Caucasian counterparts.     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers

Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design.No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST.These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.Presented in part at the Nineteenth Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, NV, November 4–8, 1990     

Adinazolam pharmacokinetics and behavioral effects following administration of 20–60 mg oral doses of its mesylate salt in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam were studied in 15 normal, healthy, non-obse volunteers. Placebo capsules and capsules containing 20, 40, and 60 mg adinazolam mesylate were administered as single oral doses in a randomized, 4-way crossover design. Plasma concentrations of adinazolam and mono-N-desmethyladinazolam (NDMAD) were determined by HPLC. Psychomotor performance and memory tests were performed and the degree of sedation assessed at designated times following drug administration. Adinazolam and NDMAD pharmacokinetics were linear throughout the dosage range studied. The ratio of NDMAD to adinazolam area under the curve was approximately 4:1. Dose-related decrements in psychomotor performance and memory were observed up to 8h after dosing (P<0.025 in all cases). Psychomotor performance decrements correlated more closely with NDMAD plasma concentrations than with adinazolam concentrations. These results suggest that NDMAD is responsible for a significant degree of the sedative and psychomotor effects observed after the administration of adinazolam.     

Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.     

Extent and Variability of the First-Pass Elimination of Adinazolam Mesylate in Healthy Male Volunteers

The pharmacokinetics of adinazolam and N-desmethyladinazolam (NDMAD) were studied in 14 healthy male volunteers who received 15 mg adinazolam mesylate orally as a solution and 5 mg adinazolam mesylate intravenously in a crossover design. Two weeks prior to the crossover study, each subject received 5 mg/kg indocyanine green (ICG) as an intravenous bolus injection to estimate liver blood flow. The absolute bioavailability (F), calculated as the dose-corrected ratio of oral to iv adinazolam area under the curve (AUC) values, was found to be 39%. NDMAD AUC values were similar following oral and iv administration, and adinazolam mean absorption time was approximately 0.77 hr. Thus, adinazolam is completely and rapidly absorbed after oral administration in man; the incomplete bioavailability is due to first-pass metabolism. Mean liver blood flow, adinazolam systemic clearance, blood/plasma ratio, and extraction ratio were 1189 ml/min, 498 ml/min, 0.70, and 0.57, respectively. The extraction ratio agrees with that calculated as 1-F (0.62), suggesting that the liver is primarily responsible for first-pass metabolism of adinazolam. The unbound fraction of adinazolam in plasma was 0.31 (range, 0.25–0.36); adinazolam free intrinsic clearance (a reflection of metabolic capacity) was 4285 ml/min (range, 2168–6312 ml/min). These results suggest that the majority of the variability in adinazolam plasma concentrations following oral administration is due to the variability in the metabolic capacity of the liver for adinazolam, rather than variability in plasma protein binding.     

Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the beta (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased beta EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.     

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.     

Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine

Objective: In a double blind, randomised, placebo-controlled, cross-over study 12 healthy male volunteers were allocated to receive felodipine + placebo, cyclosporine + placebo, and felodipine + cyclosporine in order to investigate the interaction between the calcium channel blocker felodipine and cyclosporine as it affects the pharmacokinetics of felodipine, dehydrofelodipine, and cyclosporine, and 24-hour blood pressure measurements. Methods: Single doses of cyclosporine (capsules, 5 mg/kg body weight) and of felodipine (extended release (ER) tablets 10 mg) were given at a 1–2 week interval. Plasma drug concentrations were followed for 2 days after drug intake. Results: For cyclosporine, C_max was increased after combined treatment (16%) compared to cyclosporine alone, but felodipine did not influence other kinetic parameters of cyclosporine. For felodipine, combined treatment with cyclosporine and felodipine increased AUC and C_max (58% and 151%, respectively) and lowered mean residence time (24%) significantly compared to felodipine alone. For the metabolite dehydrofelodipine, too, AUC and C_max were increased after the combined treatment (43% and 94%, respectively). Mean 24-hour systolic and diastolic blood pressures were significantly lower after felodipine, both when felodipine was given alone (121/68 mmHg) and in combination with cyclosporine (122/68 mmHg) compared to cyclosporine alone (127/73 mmHg). Conclusion: A combined single dose of cyclosporine and felodipine in healthy subjects increased the AUC and C_max of felodipine suggesting a cyclosporine-induced decrease in the first-pass metabolism of felodipine, whereas the AUC of cyclosporine was only slightly increased by felodipine. Received: 28 August 1995/Accepted in revised form: 18 December 1995     

Nefazodone pharmacokinetics: assessment of nonlinearity,intra-subject variability and time to attain steady-state plasma concentrations after dose escalation and de-escalation

Objective: The time required to reach steady-state plasma levels after an increase and a subsequent decrease in the dose of nefazodone, an antidepressant drug with nonlinear pharmacokinetics, was assessed in 24 healthy, male volunteers. Methods: Each subject was administered 100 mg nefazodone hydrochloride b.i.d. (q 12 h) from study day 1 to 7, 200 mg b.i.d. from study day 8 to 14 and 100 mg b.i.d. from study day 15 to 21. Trough (C_min blood samples were obtained just prior to the morning dose on days 4–7, 11–14 and 16–21 to evaluate the attainment of steady state. Serial blood samples were collected for 12 h after the morning dose on days 7, 14, 16, 18 and 21 for pharmacokinetic analysis of plasma levels of nefazodone (NEF) and its metabolites, hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazoledione (DIONE), which were determined by validated HPLC/UV assay methods. The C_min results indicated that when nefazodone was administered at a dose of 100 mg b.i.d., steady-state plasma levels of parent compound and its metabolites were attained by the 4th day (i.e., after six doses) and when the dose was increased from 100 mg b.i.d. to 200 mg b.i.d. and then decreased back to 100 mg b.i.d., new steady-state plasma levels were also reached by the beginning of the 3rd or 4th day of each regimen. Consistent with the attainment of steady-state data, there were no statistically significant differences in C_max or AUC values for nefazodone or its metabolites between study days 7, 18 and 21. Also consistent with the known nonlinear pharmacokinetics of nefazodone, the mean nefazodone steady-state C_max and AUC values for the 200-mg dose were three fold and four fold greater, respectively, than those at the 100-mg dose level. Intrasubject variability (% cv) for NEF and its metabolites ranged from 13% to 24% for C_max and AUC after 100 mg b.i.d.. Intersubject variability was considerably greater and ranged from 29% to 131% for C_max and AUC after the same dose. Received: 12 June 1995/Accepted in revised form: 2 October 1995     

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.     

Gender does not affect the degree of induction of tirilazad clearance by phenobarbital

Objective: Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F). Methods: Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg⋅kg⁻¹ tirilazad mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. Results: Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC_0–6 for U-89678 after the last tirilazad mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. Conclusion: The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response. Received: 11 July 1995/Accepted in revised form: 6 October 1995     

Pharmacokinetics of flosequinan in patients with heart failure

Objective: The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure. Results: After a single dose of 100 mg, C_max of the parent compound (2.52 mg ⋅ l⁻¹) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (C_max 8.4 vs 3.21 mg ⋅ l⁻¹). No adverse effects were observed. Conclusion: It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity. Received: 16 January 1995/Accepted in revised form: 30 October 1995     

Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers

Objective: This study was performed to assess whether coadminstration with grapefruit juice significantly affects the pharmacokinetics of amlodipine, a dihydropyridine class calcium antagonist with slow absorption, distribution and low plasma clearance. The primary objective was to evaluate whether short exposure to grapefruit juice could affect the metabolism of amlodipine to an extent similar to that previously demonstrated for other dihydropyridines (e.g. felodipine, nisoldipine, nitrendipine). Methods: Twelve healthy male volunteers followed a randomised, open crossover study design, comparing the effect of a single oral dose of amlodipine (5 mg) taken together with a glass of grapefruit juice (250 ml) vs water. Blood samples to determine plasma concentration were taken and blood pressure (BP) and heart rate (HR) were measured throughout the study. Results: When amlodipine was coadministered with grapefruit juice, C_max was 115% and AUC(0–72 h) was 116% compared with water, but t_max was not significantly changed. There were no significant differences in BP and HR between the two treatments. A small decrease in diastolic BP, however, was observed in both treatments 4–8 h after drug administration, coinciding with C_max, but this was normalised after 12 h. The BP reduction seen was compensated by a slight increase in HR, which remained throughout the study. Conclusion: An interaction between grapefruit juice and amlodipine was demonstrated. The haemodynamic data showed that a dose of 5 mg was sufficient to achieve a BP reduction in healthy subjects, but the increase in amlodipine plasma concentration seen after intake of grapefruit juice was too small to significantly affect BP or HR. The clinical significance of this food/drug interaction, however, cannot be ignored since there is considerable variation between individuals and a more extensive intake of grapefruit juice might give more pronounced effects. Received: 7 November 1995/Accepted in revised form: 27 March 1996     

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. Results: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: C_max = 2.3 ng⋅ml⁻¹, t_max = 2.8 h; slow release: C_max = 1.2 ng⋅ml⁻¹, t_max = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng⋅ml⁻¹). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted. Received: 14 December 1995/Accepted in revised form: 26 March 1996     

Multiple-dose clinical pharmacology of the catechol-O-methyl-transferase inhibitor tolcapone in elderly subjects

Objective: The purpose of this study was to assess the multiple-dose clinical pharmacology of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor, in elderly subjects. Methods: The drug was administered orally t.i.d. for 7 days to four sequential groups of eight elderly subjects (gender ratio1:1) at doses of 100, 200, 400 and 800 mg in a double-blind, randomised, placebo-controlled, ascending-multiple-dose design. On days 2 and 7, a single dose of levodopa/benserazide 100/25 mg was given 1 h after the first intake of tolcapone. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa were determined during the course of the study in conjunction with COMT activity in erythrocytes. Results: Tolcapone was well tolerated at all dose levels, with a slight increase in gastrointestinal adverse events in females at higher doses. The drug was rapidly absorbed and eliminated and showed no changes in pharmacokinetics with time during multiple doses of 100 and 200 mg t.i.d. At doses of 400 and 800 mg t.i.d., tolcapone accumulated moderately as reflected in increased C_max and AUC values. Despite the long half-life of 3-O-methyltolcapone (39 h), only minor accumulation occurred due to suppression of its formation by tolcapone. The pharmacodynamics of tolcapone did not change during the week of treatment as reflected in inhibition of COMT activity in erythrocytes, the derived parameters of the plasma concentration-effect relationship (inhibitory E_max model with constant EC₅₀ values) and the effect on levodopa pharmacokinetics (1.6 to 2.5-fold increase in bioavailability). This suggests the absence of tolerance development and the insignificance of the altered pharmacokinetics at 400 and 800 mg t.i.d. with regard to the pharmacodynamics. Conclusion: The results of this study offer promising perspectives for the application of tolcapone as adjunct therapy to levodopa in the treatment of Parkinson’s disease. Received: 28 August 1995/Accepted in revised form: 23 October 1995     

Effect of diprafenone on the pharmacokinetics of digoxin

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 × 1 mg) or digoxin and diprafenone (3 × 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone). Blood and urine samples were collected for pharmacokinetic analyses. Diprafenone caused a statistically significant increase in digoxin trough concentrations [1.4 (SD 0.2) vs 1.6 (0.3) ng ⋅ml⁻¹], AUC_0–24 values [41 (7) vs 48 (9) ng⋅h⋅ml⁻¹ and C_ss-max [3.9 (0.6) vs 5.5 (0.9) ng⋅ml⁻¹]. In all volunteers the parameters tended to return to the original values after administration of diprafenone was discontinued [1.4 (0.3) ng⋅ml⁻¹, 39 (11) ng⋅h⋅ml⁻¹, and 3.9 (1.1) ng⋅ml⁻¹ for trough concentration, AUC_0–24 and C_max respectively]. The mean relative magnitude of the increase in AUC_0–24 and trough concentration values corresponded to the mean relative decrease in the renal clearance of digoxin (in both cases approximately 20%). This suggests that the increase in AUC and C_ss was caused by reduced renal clearance of digoxin. Received: 10 July 1995 /Accepted in revised form: 5 October 1995     

A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients

Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml^–1, C_max was 832 vs 871 ng⋅ml^–1 and t_max was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely. Received: 19 October 1995/Accepted in revised form: 8 January 1996