Effect of fluoxetine on pharmacokinetics of ritonavir.

The potential interaction between fluoxetine, a known inhibitor of cytochrome P-450 isoform 2D6 (CYP2D6), and ritonavir, a human immunodeficiency virus type 1 protease inhibitor, was evaluated in this open-label study. Sixteen male and female subjects ranging in age from 18 to 40 years completed the study. Subjects received single doses of 600 mg of ritonavir on days 1 and 10. On study days 3 to 10, all subjects received 30 mg of fluoxetine every 12 h for a total of 16 consecutive doses. Serial blood samples for determination of ritonavir concentrations in plasma were collected after the administration of ritonavir on days 1 and 10. A limited number of blood samples for determination of fluoxetine and norfluoxetine concentrations were collected after administration of the morning dose on day 10. A statistically significant increase (19%) in the ritonavir area under the concentration-time curve (AUC) was observed with concomitant fluoxetine administration, with individual changes ranging from -12 to +56%. The change in the ritonavir AUC with concomitant fluoxetine administration was positively correlated with the norfluoxetine 24-h AUC (AUC24) (r2 = 0.42), the norfluoxetine/fluoxetine AUC24 ratio (r2 = 0.53), and the fluoxetine elimination rate constant (r2 = 0.65), with larger increases in the ritonavir AUC tending to occur with higher norfluoxetine concentrations and higher fluoxetine elimination rate constants. The effect of fluoxetine appeared to be larger in subjects with the CYP2D6 wt/wt genotype. There was little or no effect on the time to maximum drug concentration (Cmax) in serum, Cmax, and the elimination rate constant of ritonavir with concomitant fluoxetine administration. Considering the magnitude of the change observed, no ritonavir dose adjustment is recommended during concomitant fluoxetine administration.

Effect of infusion duration on valproate pharmacokinetics.

The pharmacokinetics of intravenously administered valproic acid (VPA) were investigated in 16 healthy male volunteers in a single-dose, fasting, four-period, randomized, double-blind, placebo-controlled, parallel design study. Subjects were randomly assigned to be infused a single dose of sodium valproate equivalent to 1000 mg VPA or placebo over each of four different time periods. Valproate concentrations in plasma were determined using gas chromatography with flame ionization detection. The pharmacokinetic parameters were determined by both non-compartmental and model-dependent techniques. Analyses of variance (ANOVAs) were performed to detect any statistical differences among the regimens. Overall, the pharmacokinetic of valproate were similar after infusions of 5, 10, 30, and 60 min, with an average terminal-phase half-life of 15.9 h. There were modest differences in overall clearances among the regimens, with the 5 min infusion producing a mean area under the plasma concentration-time curve (AUC; 1877 micrograms.h ml-1) that was significantly (13 to 16 per cent) higher than the means for the longer infusions (1614-1656 micrograms.h ml-1). Differences in distribution were also noted as a function of infusion duration. The shortest duration produced a significantly smaller terminal volume of distribution (12.8 vs 14.2-15.1 l) and more rapid tissue equilibration. The alpha-phase rate constant declined from a mean of 5.1 h-1 after the 5 min infusion to a mean of 0.9 h-1 after the 60 min infusion. The distributional differences are almost certainly related to the saturable protein binding of valproate. However, the lower clearance after the 5 min infusion indicates that there may have also been partial saturation of one of the metabolic pathways of valproate during the distributive phase, and that the increase in fu was smaller than the decrease in CL'int, such that the product of fu.CL'int showed a net decrease.

Absorption characteristics of a new valproate formulation: divalproex sodium-coated particles in capsules (Depakote Sprinkle).

To determine the absorption characteristics of a new dosage form of divalproex sodium consisting of coated particles in a pull-apart capsule (Depakote Sprinkle, Abbott Laboratories, North Chicago, IL), two absorption studies were conducted in adult volunteers. Ten fasting men participated in a single-dose, crossover study comparing absorption from Sprinkle capsules versus enteric-coated tablets (study 1). Eleven men participated in a multidose study (study 2) in which Sprinkle capsules or enteric-coated tablets were given once every 24 hours for three doses under fasting and nonfasting conditions. In study 1, the extent of absorption from Sprinkle capsules equalled that from enteric-coated tablets. Compared to enteric-coated tablets, Sprinkle capsules had earlier absorption onset, 1 versus 2.6 hours (P less than .05), slightly slower absorption rate, time to reach peak (tmax) of 4.0 versus 3.4 hours (P less than .1), and lower maximum peak plasma drug concentration (Cmax), 20.7 versus 25.9 mcg/mL (P less than .05). In study 2, food intake did not affect onset or extent of absorption nor maximum concentration, but did slow rate of absorption. Time to reach peak concentration was 2.7 hours for tablet (fasting), 3.3 hours for capsule (fasting), and 4.8 hours for capsule (nonfasting) (P less than .05). Intrasubject absorption performance from the three doses was highly consistent, regardless of food intake. These data indicate that Sprinkle capsules possess desirable absorption characteristics in a form that makes ingestion easier for patients who have difficulty taking other valproate dosage forms.

Metabolism and disposition of clarithromycin in man.

The metabolic fate and pharmacokinetics of clarithromycin following a single 250- or 1200-mg oral dose of 14C-clarithromycin were studied in six healthy adult males. Peak plasma levels of clarithromycin averaged 0.6 microgram/ml after the low dose and 2.7 micrograms/ml after the high dose. The AUC of clarithromycin increased 13-fold, with the 4.8-fold increase in dose, while the plasma half-life increased from 4.4 hr to 11.3 hr. The major metabolite in plasma and urine was the microbiologically active 14-hydroxylated-R epimer of clarithromycin. After 5 days, a mean of 38% of the low dose (18% as clarithromycin) and 46% of the high dose (29% as clarithromycin) was recovered in the urine, with approximately one-third eliminated during the first 24 hr. The nature of the urinary and fecal metabolites revealed the involvement of three metabolic pathways, viz. 1) hydroxylation at the 14-position to form the R and S epimers, 2) N-demethylation, and 3) hydrolysis of the cladinose sugar. Secondary metabolism via these pathways was also evident. The overall recovery of metabolites, but not total radioactivity, decreased 42% after the high dose. The nonlinear pharmacokinetic behavior of clarithromycin and the decrease in metabolite production suggest that clarithromycin metabolism can be saturated at high doses.

Ventilation during prolonged hypercapnia in the rat.

Awake rats, with chronically implanted arterial catheters and abdominal thermistors, were continuously exposed to 5 or 7% CO2 in air in an environmental chamber for up to 3 wk. To obtain measurements, rats were transferred to a body plethysmograph flushed with the same CO2 mixture, and, after stabilization, O2 consumption (Vo2), ventilation (VE), and arterial blood gases (ABG) were determined. After 2-h exposure, VE, tidal volume/inspiratory time (VT/TI), and VO2 were significantly increased. Thereafter, VE and VT/TI fell gradually with time, the largest decrease occurring within the 1st day of exposure. The increase in VO2 was maintained up to 3 days and then declined. ABG revealed extensive metabolic compensation for respiratory acidosis within 3-7 days. delta(VT/TI) correlated well with delta VE and delta [HCO3]a (P less than 0.05). It is likely that the gradual return toward normal pHa reduces ventilatory drive (VT/TI), which in turn lowers VE. Estimated alveolar ventilation did not decrease consistently with time in parallel with VE, suggesting that the early ventilatory overshoot might also be due to an increase in dead space.