Effect of probenecid on dyphylline elimination.

Dyphylline is a methylxanthine bronchodilator with such a short a biologic t 1/2 that development of practical dosing regimens has been difficult. Because its rapid renal elimination suggests active secretion, the effect of 1 gm probenecid on single-dose elimination kinetics of dyphylline was determined. Twelve subjects (six male, six female) participated in a crossover design. Subjects were their own controls and received dyphylline, 20 mg/kg orally, alone and after probenecid. The dyphylline t 1/2 increased from 2.57 +/- 0.45 to 4.88 +/- 1.2 hr, whereas the elimination rate constant decreased from 0.276 +/- 0.056 to 0.150 +/- 0.037 hr-1 after probenecid. There was no significant change in the dyphylline apparent volume of distribution. Dyphylline total body clearance fell from 173 +/- 20 to 95 +/- 12 ml/kg . hr. The combined use of these drugs may lead to a practical dyphylline dosage schedule in aminophylline-hypersensitive patients or those incapacitated by theophylline gastrointestinal side effects.

Effects of cimetidine on caffeine disposition in smokers and nonsmokers.

The absorption, distribution, and elimination of caffeine, 2 mg/kg by mouth, were evaluated in six smokers and six nonsmokers before and on the fourth day of administration of cimetidine, 300 mg by mouth every 6 hr. Caffeine absorption, assessed by the maximal serum caffeine concentration (C max) and the time to reach Cmax (t max), was very rapid relative to elimination. The total body clearance (TBC) of caffeine was higher (2.49 +/- 0.35 and 1.59 +/- 0.19 ml/kg/min, P less than 0.05) and the elimination half-life (t1/2) shorter (190 +/- 15 and 276 +/- 30 min, P less than 0.05) in smokers than nonsmokers, but Cmax, tmax, and the apparent volume of distribution (Vd, app) did not differ (P greater than 0.05). Cimetidine decreased the TBC of caffeine by 31% (to 1.73 +/- 0.28 ml/kg/min, P less than 0.05) and by 42% (to 0.92 +/- 0.11 ml/kg/min, P less than 0.01) in smokers and nonsmokers. The increases in t1/2 were 45% (to 276 +/- 25 min, P less than 0.05) and 96% (to 542 +/- 123 min, P less than 0.05). Cmax, tmax, and Vd, app were unaffected by cimetidine. Caffeine induced similar slight increases in blood pressure and pulse rate in smokers and nonsmokers both before and during cimetidine dosing.

Clovoxamine kinetics in an early clinical trial.

Elimination kinetics of the new antidepressant clovoxamine were determined in a preliminary clinical trial in 10 depressed patients. When final oral doses of 50 mg clovoxamine fumarate were given, the mean peak steady-state plasma concentration was about 60 ng/ml after 3 hr. Clovoxamine elimination proceeded by an apparent single-phasic, first-order decline with a mean t1/2 of 9.5 +/- 2.8 hr. One subject had an unusually long t1/2 (31.5 hr) and had correspondingly high clovoxamine plasma concentrations. The mean apparent volume of distribution (Vd) calculated from oral dosage was 19.5 +/- 6 l/kg, but one atypical subject had an apparent Vd of 96 l/kg. The mean apparent oral clearance was 25.5 +/- 12.5 ml/min/kg. These parameters should be of assistance in planning dosage regimens and monitoring therapeutic blood levels according to kinetic principles. Atypical clovoxamine kinetics can be associated with abnormally high or low blood levels and could therefore lead to variability in clinical response.

Synthesis and peripheral cardiovascular action of cis- and trans-2-(3,4-dimethoxybenzyl)cyclopentylamine hydrochlorides.

The hydrochlorides of cis- and trans-2-(3,4-dimethoxybenzyl)cyclopentylamine have been synthesized. They are transient hypotensive agents with early and delayed depressor effects and antagonists of dopamine-induced vasodepression. In the atropinized and phenoxybenzamine-treated dog, the threshold dose for hypotension was 3-5 mumol/kg. The early depressor phases were attenuated variably by different types of antagonists, suggesting a nonspecific interaction with blood pressure regulation mechanisms. Cimetidine blocked the delayed depressor phases, consistent with endogenous histamine release. The cis amine hydrochloride was three to four times more potent than its trans isomer as a peripheral dopamine blocking agent. Cimetidine but not diphenhydramine interfered with this effect.

2,5-Bis(3,4-dimethoxybenzyl)cyclopentylamine, a peripheral dopamine blocking agent.

2,5-Bis(3,4-dimethoxybenzyl)cyclopentylamine hydrochloride has been synthesized. The intermediate 2,5-bis-(3,4-dimethoxybenzyl)cyclopentanone was formed in 91.8% yield using a sodium methoxide catalyzed aldol condensation and catalytic reduction. The oxime of this ketone was catalytically hydrogenated to the amine which was converted to the hydrochloride (76%). The amine hydrochloride was found to be an effective antagonist to the low-dose hypotensive effect of dopamine; the half-life of this effect was 18 min. At dopamine doses of 3 mg/kg in the atropinized and phenoxybenzamine treated dog, the ED50 for blockade was 4--5 mumol/kg. In direct contrast to its peripheral dopamine blocking activity, the compound potentiates apomorphine-induced stereotypy.

Dyphylline elimination kinetics in lactating women: blood to milk transfer.

A population of 20 normal lactating females between the ages of 20 and 35 years was treated with a single 5 mg/kg intragluteal dose of dyphylline, 7-(2,3-dihydroxypropyl)theophylline. The distribution of the drug between blood and milk and its pharmacokinetics of elimination were determined. The apparent volume of distribution (Vd) of dyphylline was found to be 0.505 +/- 0.162 l./kg, the elimination rate constant (Kel) was 0.228 +/- 0.055 hr-1, the biological half-life (t1/2) was 3.21 +/- 0.76 hr, and the total body clearance (CI) was 0.109 +/- 0.036 l./kg/hr. The ratio described by dyphylline distribution between milk and serum (M/S) was 2.08 +/- 0.52. The elimination rate from milk was equivalent to that from blood.

The effects of erythromycin on theophylline elimination in normal males.

The effects of three erythromycin preparations on theophylline elimination kinetics were examined in 23 male subjects. Subjects received 6 mg/kg of the theophylline elixir orally and elimination kinetics were determined. The population was then randomized to receive either a lactose placebo, erythromycin base, erythromycin stearate, or erythromycin ethylsuccinate. Each 250-mg preparation was given four times a day for six days. On day seven, a repeat kinetic study was performed. The mean theophylline half-life of controls was 7.8 +/- 2.6 hours. The half-life increased significantly in all erythromycin treatment groups. The increase for the base, stearate, and ethylsuccinate groups was 51.7, 21.3, and 60.3 per cent, respectively. The total body theophylline clearance decreased significantly in all treatment groups. This was not associated with biochemical evidence of hepatitis. Three of four smokers who received erythromycin manifested no increase in theophylline half-life, in contrast to one of 13 nonsmokers. There was no difference in the percentage theophylline bound to serum protein for any of the erythromycin treatment groups or controls as determined by ultracentrifugation.