B. Verburg-Ochs

Propranolol interactions with diazepam, lorazepam, and alprazolam

Healthy subjects received single doses of diazepam (5 to 10 mg iv), lorazepam (2 mg iv), or alprazolam (1 mg orally) on two occasions, once in the control state and once with propranolol, 80 mg three times a day. Compliance with the propranolol regimen was verified by measurement of serum propranolol levels (overall X̄: 100 ng/ml) and by reduction in sensitivity to intravenous metaproterenol to one‐thirtieth that of the control value. Propranolol prolonged diazepam elimination t½ (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168‐hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 µg/ml · hr). Propranolol had no significant effect on lorazepam t½ (13.2 and 12.7 hr) or clearance (1.33 and 1.36 ml/min/kg), nor on alprazolam t½ (15.9 and 18.5 hr) or clearance (1.1 and 0.8 ml/min/kg). Thus propranolol induces a small but significant reduction in clearance of diazepam, biotransformed mainly by the oxidative reaction of N‐demethylation. Propranolol does not impair lorazepam clearance by glucuronide conjugation nor that of alprazolam by aliphatic hydroxylation.

Single and multiple dose kinetics of clobazam, and clinical effects during multiple dosage

SummarySixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.

Chronic Treatment with Fluvoxamine, Clovoxamine, and Placebo: Interaction with Digoxin and Effects on Sleep and Alertness

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self‐rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half‐life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half‐life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P < .05). Self‐ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.

Differential Effects of Isoniazid and Oral Contraceptive Steroids on Antipyrine Oxidation and Acetaminophen Conjugation

Factors influencing hepatic oxidation of antipyrine and conjugation of acetaminophen were evaluated in volunteers who received 1.0 g of antipyrine intravenously and on a different occasion a 650 mg intravenous dose of acetaminophen. In study one, subjects received both drugs in the control state and at another time during coadministration of isoniazid (INH), 180 mg daily. In control versus INH conditions, mean clearance of antipyrine was reduced from 0.67 to 0.60 ml/min/kg as was clearance of acetaminophen from 4.97 to 4.23 ml/min/kg, but these differences were not statistically significant. In study two, females on low-dose estrogen oral contraceptives (OC) and drug-free controls matched for age received both drugs. Compared to controls, OC users had reduced total clearance of antipyrine (0.71 vs. 0.50 ml/min/kg; p less than 0.005) and prolonged antipyrine t1/2 (9.6 vs. 13.3 h; p less than 0.005). For acetaminophen, however, OC users had higher clearance (5.2 vs. 6.1 ml/min/kg) and shorter t1/2 (2.2 vs. 1.9 h) although differences did not attain statistical significance. Clearance of antipyrine and acetaminophen across both studies was not statistically significantly correlated within individuals (r = 0.22). The capacities for drug oxidation and conjugation appear to be controlled by different mechanisms.

Nifedipine: Kinetics and dynamics after single oral doses

SummarySerum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 µg/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3–12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.

Disposition of clotiazepam: Influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol

SummaryFactors influencing the disposition of clotiazepam in man were evaluated in a series of pharmacokinetic studies in healthy volunteers given a single 5 mg dose. Old age caused an increased volume of distribution of clotiazepam in women, and its clearance tended to be reduced in elderly men. Use of oral contraceptives, cimetidine, isoniazid or a single dose of ethanol had no significant effect on the kinetics of clotiazepam. Although clotiazepam is biotransformed by microsomal oxidation, its clearance appears to be relatively uninfluenced by factors known to alter the clearance of other oxidized benzodiazepines.

Effect of alprazolam on digoxin kinetics and creatinine clearance

Eight healthy men received a single, 1.25 mg dose of digoxin on two occasions, once in an otherwise drug‐free control state and again while concurrently receiving alprazolam, 1.5 mg/day. There was no significant difference between control and alprazolam conditions in digoxin volume of distribution (11.0 vs. 11.2 L/kg), elimination t½ (46 vs. 41 hours), or total clearance from serum (2.8 vs. 3.6 ml/min/kg). Alprazolam coadministration slightly reduced mean 96‐hour urinary excretion of digoxin (37.6% vs. 30.9% of dose; P < 0.01), but there was no significant difference between treatment conditions in projected total cumulative excretion of digoxin (45.2% vs. 40.9% of dose) or in renal clearance of digoxin (1.23 vs. 1.44 ml/min/kg). Creatinine clearance also did not differ between the control and alprazolam conditions (164 vs. 142 ml/min). Thus therapeutic doses of alprazolam do not significantly alter digoxin clearance in healthy man.

Kinetics of 1,2-Dinitroglycerin Following Sustained Release Nitroglycerin: Influence of Propranolol and Metoprolol* **

SummaryTen healthy volunteers ingested a single 18-mg oral dose of sustained release nitroglycerin (TNG) (Giulini-Pharma) on three occasions: once in the control state, once during coadministration of propranolol (80-mg three times daily), and once during coadministration of metoprolol (100-mg twice daily). The degree of beta adrenergic blockade was evaluated by the metaproterenol infusion test. Plasma concentration of TNG and its major metabolite, 1,2-dinitroglycerin (DNG), during 12 h after each dose were measured by gas chromatography-mass spectrometry. Intact TNG was not detected in the plasma of any patient. The major metabolite, DNG, was easily measurable in blood, and had a biphasic plasma concentration profile. Coadministration of the beta-blockers had no influence on any of the kinetic variables for DNG. The mean values during control, propranolol, and metoprolol trials of DNG elimination half-life were: 1.35, 1.10, and 1.09 h; total area under the curve: 42, 38, and 42 ng/ml × h; oral clearance: 6.6, 7.2, and 6.4 liters/min. Thus TNG when administered as a sustained release oral preparation is rapidly and completely transformed to DNG. There was no pharmacokinetic interaction between sustained release TNG and two commonly used beta-blocking agents, suggesting that any clinical interaction that may-occur between sustained release nitroglycerin and beta-blocking agents is pharmacodynamic rather than pharmacokinetic in nature.

Effect of Ketanserin on the Kinetics of Digoxin and Digitoxin

The influence of the serotonin antagonist ketanserin on the kinetics of digoxin and digitoxin were evaluated in healthy volunteers. Subjects received a single intravenous dose of digoxin (1.25 mg) or of digitoxin (1.0 mg) on two occasions: once in the control state, and again during treatment with ketanserin, 40 mg twice daily. Ketanserin caused a prolongation of digoxin elimination half-life (50 versus 40 h) and reduction in clearance (2.4 versus 3.7 ml/min/kg), but differences were not significant. For digitoxin, ketanserin caused a small but significant (p less than 0.005) increase in volume of distribution (0.89 versus 0.78 L/kg), but no significant effect on half-life (7.0 versus 6.8 days), or clearance (0.063 versus 0.059 ml/min/kg). Thus, ketanserin coadministration is not likely to alter steady-state concentrations of digoxin or digitoxin during clinical use of these two digitalis glycosides.

Propranolol Interactions with Diazepam, Lorazepam and Alprazolam

Healthy subjects received single doses of diazepam (5 to 10 mg iv), lorazepam (2 mg iv), or alprazolam (1 mg orally) on two occasions, once in the control state and once with propranolol, 80 mg three times a day. Compliance with the propranolol regimen was verified by measurement of serum propranolol levels (overall means: 100 ng/ml) and by reduction in sensitivity to intravenous metaproterenol to one-thirtieth that of the control value. Propranolol prolonged diazepam elimination t1/2 (58 and 49 hr), reduced its clearance (0.20 and 0.24 ml/min/kg), and increased the 168-hr AUC for desmethyldiazepam, the major metabolite of diazepam (5.63 and 4.81 micrograms/ml . hr). Propranolol had no significant effect on lorazepam t1/2 (13.2 and 12.7 hr) or clearance (1.33 and 1.36 ml/min/kg), nor on alprazolam t1/2 (15.9 and 18.5 hr) or clearance (1.1 and 0.8 ml/min/kg). Thus propranolol induces a small but significant reduction in clearance of diazepam, biotransformed mainly by the oxidative reaction of N-demethylation. Propranolol does not impair lorazepam clearance by glucuronide conjugation nor that of alprazolam by aliphatic hydroxylation.