In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.

The single-dose pharmacokinetics of intravenously administered ampicillin (2.0 g) and sulbactam (1.0 g) were studied in normal subjects and in patients with various degrees of creatinine clearance (CLCR). Six normal subjects (CLCR, >60 ml/min), six patients with mild renal failure (CLCR, 31 to 60 ml/min), four patients with severe renal failure (CLCR, 7 to 30 ml/min), and four patients requiring maintenance hemodialysis (CLCR, <7 ml/min) were studied. The terminal half-lives for ampicillin and sulbactam more than doubled in patients with severe renal failure compared with subjects with normal renal function and mild renal insufficiency. CLCR significantly correlated with ampicillin (r = 0.88) and sulbactam (r = 0.54) total body clearance. Mean steady-state volume of distribution and nonrenal clearance for ampicillin and sulbactam were not affected by renal function. Hemodialysis approximately doubled the ampicillin and sulbactam total body clearance. Mean totals of 34.8 4.0% of the ampicillin dose and 44.7 + 3.2% of the sulbactam dose were removed during a 4-h hemodialysis treatment. A slight rebound in concentrations in serum after hemodialysis was observed for both drugs in all four subjects. In hemodialysis patients, the ampicillin half-life was 17.4 8.0 h and the sulbactam half-life was 13.4 + 7.4 h. The ampicillin and sulbactam half-lives were appreciably altered during the hemodialysis period (means of 2.2 and 2.3 h, respectively). The nearly parallel decrease in total body clearance, with volume of distribution and nonrenal clearance remaining relatively constant, suggests that the same ratio of ampicillin to sulbactam is appropriate regardless of renal function. An adjustment of the ampicillin (2.0 g) and sulbactam (1.0 g) dose to twice daily would be appropriate in patients with a CLCR between 7 and 30 ml/min. Doses should be given every 24 h for those undergoing maintenance hemodialysis. On hemodialysis days, doses should be given after hemodialysis.Ampicillin-sulbactam is a broad-spectrum, bactericidal, P-lactamase-resistant antimicrobial combination with potent activity against Haemophilus influenzae, Branhamella catarrhalis, Neisseria species, and most gram-positive and anaerobic pathogens (3,9,10,13). Coadministration of sulbactam appears to have very little effect on the pharmacokinetics of ampicillin, suggesting that coadministration of the sulbactam will not affect the usual dosing regimens for ampicillin (5). The pharmacokinetics of sulbactam are very similar to those of ampicillin in subjects with normal renal function (2,4,5,11,14). The purposes of this study were to evaluate the pharmacokinetics of ampicillin-sulbactam in subjects with various degrees of renal function to evolve dosage guidelines and to determine the effect of hemodialysis on the clearances of ampicillin and sulbactam.

The influence of the method of cimetidine administration on theophylline disposition was studied in nine healthy, cigarette smoking male volunteers. The treatment phases consisted of: A) theophylline alone, B) theophylline plus intermittent cimetidine therapy (300 mg IV every 6 hr), and C) theophylline in combination with continuous infusion cimetidine (50 mg/hr). Theophylline (4.8 mg/kg) was administered intravenously as aminophylline over 30 minutes during each treatment phase. During study phases B and C subjects received 48 hours of cimetidine therapy beginning 24 hours prior to theophylline dosing. Blood samples for determination of theophylline concentrations were collected serially over 24 hours. Serum theophylline concentrations were determined in duplicate using fluorescence polarization immunoassay (Abbott Diagnostic TDx). The average age of the subjects was 27.4 +/- 4.7 years, and the individual smoking histories ranged from 0.5 to 1.5 packs per day (average 0.89 +/- 0.33). The mean (+/- SD) body weight was 79.1 +/- 8.2 kg and all subjects were within 20% of their ideal body weight. Theophylline pharmacokinetic parameters were determined using noncompartmental analysis. ANOVA for repeated measures and Tukey's multiple comparison test were used for statistical analysis. The mean (+/- SD) theophylline clearance for each of the treatment groups was: 1.4 +/- 0.4, 1.2 +/- 0.3, and 1.2 +/- 0.2 ml/min/kg for phases A, B and C, respectively. Cimetidine decreased the clearance of theophylline, however, theophylline clearance was not statistically different between regimens B and C. Thus, the method of cimetidine administration (intermittent versus continuous infusion) did not influence the magnitude of the drug-drug interaction.