A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam.

Linezolid, a new oxazolidinone antimicrobial agent, has a spectrum of activity encompassing a wide variety of Grampositive bacteria. The purpose of this study was to evaluate the pharmacokinetics of linezolid and aztreonam, an antimicrobial agent with selective activity against Gram-negative bacteria, when given alone and in combination. Healthy subjects were randomized to receive single, 30-minute intravenous infusions of (1) linezolid 375 mg, (2) aztreonam 1000 mg, and (3) linezolid 375 mg plus aztreonam 1000 mg in an open-label, crossover manner. The only statistically significant differences observed with combination treatment relative to each drug alone were an increase in the maximum plasma concentration of linezolid (approximately 18%) and an approximate 7% decrease in the apparent elimination rate of aztreonam, neither of which are expected to be clinically significant. In healthy subjects, the combination of linezolid and aztreonam was safe and well tolerated compared with each agent used alone. Pharmacokinetic data demonstrate that coadministration of linezolid and aztreonam does not alter the disposition of either agent under single-dose conditions. Therefore, it is not expected that a dose alteration of either agent will be necessary in a clinical setting.

Steady-state pharmacokinetic properties of pramipexole in healthy volunteers.

Pramipexole is a dopamine receptor agonist that has proved effective in the treatment of Parkinson's disease. The pharmacokinetic properties of pramipexole at steady-state concentrations were studied in 16 healthy men and women at four dose levels throughout the range recommended for Parkinson's patients. Plasma and urine samples collected within the four dose intervals were assayed for concentrations of pramipexole, using high-performance liquid chromatography. The total oral clearance for all participants was 419 mL/min. The mean volume of distribution and elimination half-life for all participants was 486 +/- 93.2 L and 12.9 +/- 3.27 hours. Concentrations of pramipexole were proportional to dose, although the drug's pharmacokinetic properties differed between men and women. The area under the concentration-time curve for each dose level was 35% to 43% greater in women, mainly because of a 24% to 27% lower oral clearance. The mean creatinine clearance in men and women was 112 +/- 12.8 mL/ min/1.73 m2 and 80.9 +/- 15.6 mL/min/1.73 m2, respectively. The renal clearance of pramipexole accounts for approximately 80% of oral clearance, and there was a significant correlation between renal and creatinine clearances. The influence of gender could not be distinguished from the influence of age and the resulting reduced creatinine clearance, but the measurement of pharmacokinetic properties produced linear results in both men and women.

Pharmacokinetics and psychomotor performance of alprazolam: concentration-effect relationship.

The relationship between the pharmacokinetics of alprazolam and dose and the relationship between the concentration of alprazolam and psychomotor performance in healthy male volunteers were investigated in this double-blind, placebo-controlled, modified crossover study. Twenty-four volunteers received placebo in Phase I and then received single 2-mg, 4-mg, 8-mg, and 10-mg doses of a sustained-release formulation in Phases II through V, according to, a crossover design. Blood samples were collected at several times throughout each phase to 48 hours after the dose; the harvested plasma was assayed for concentrations of alprazolam, 4-hydroxyalprazolam, and alpha-hydroxyalprazolam by high-performance liquid chromatography. Sedation was rated at each blood-sampling time and psychomotor performance tests, consisting of digit-symbol substitution and card-sorting tasks, were conducted at several times after each dose. Area under the concentration-time curve and peak concentration for alprazolam increased proportionally with each higher dose; clearance did not differ significantly between treatments. The concentrations of 4-hydroxyalprazolam and alpha-hydroxyalprazolam increased proportionally with dose and the combined plasma concentration of the metabolites were less than 15% of unchanged concentrations of alprazolam for all doses. Maximum sedation increased with each increase in dose up to 8 mg, and psychomotor performance decreased with each increase in dose. Performance versus concentration curves for alprazolam exhibited a clockwise hysteresis loop in contrast to the counterclockwise hystereses previously reported for both intravenous and oral doses of immediate-release tablets. Data through 6 hours after dose were well described by a sigmoid Emax model. Alprazolam exhibits linear pharmacokinetics after single oral doses of sustained-release tablets between 2 mg and 10 mg. Reversal of the concentration-effect curve to a clockwise loop suggests the counterclockwise hystereses of rapidly absorbed doses was caused by the differing distribution rates into the systemic circulation and effect site and not by metabolite activity.