Topiramate, a new antiepileptic drug effective in controlling partial-onset seizures, was administered to humans for the first time as single oral doses of 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg in a phase I safety and pharmacokinetic study. Model-independent pharmacokinetic data analysis was performed on plasma concentration and renal excretion data for topiramate. Maximum plasma concentrations (Cmax) were observed between 1.4 and 4.3 hours after administration. Mean values for plasma Cmax and area under the concentration-time curve (AUC) increased linearly with dose; however, a greater-than-proportional increase in both parameters was observed, probably due to saturable binding of the drug to erythrocytes. Mean oral clearance (Cl/F) was 22.5 to 36.1 mL/min and mean volume of distribution (Vd/F) was 38.5 to 58.0 L. Approximately 50% of the dose was excreted renally and cumulative urinary excretion increased linearly and proportionally over the 200 mg to 1,200 mg dose range. Elimination half-life (t1/2) values calculated from plasma (21.5 hrs) and urinary data (18.5 hrs) were consistent and independent of dose. Intersubject variability was low for all parameters. Renal clearance was 13.9 mL/min, suggesting that renal tubular reabsorption may be prominently involved in the renal handling of topiramate. The elimination profile of topiramate indicated that longer sampling times are necessary in future studies to more accurately determine the t1/2. Food effect studies indicated a slight reduction in the rate (approximately 10% decrease in mean Cmax and mean tmax approximately 2 hours later) but not the extent of absorption when topiramate was given with food. Topiramate demonstrates a number of favorable pharmacokinetic features, including linear and predictable dose-concentration relationships, excretion mainly as unchanged drug by the kidney, a dose-independent t1/2, low intersubject variability in pharmacokinetic parameters, and lack of clinically significant effect of food on bioavailability.

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo-controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a third study (study C), the comparability of the bioavailabilities of two oral and one intravenous levofloxacin formulations were investigated with 24 healthy male subjects in an open-label, randomized, three-way crossover study. Levofloxacin at 500 mg as a single tablet or an intravenous infusion was administered on day 1; following a 1-week washout period, subjects received the second regimen (i.e., the other oral formulation or the intravenous infusion); the third and final regimen was administered following a 1-week washout period. The concentrations of drug in plasma and urine were measured by validated high-pressure liquid chromatography methods. Pharmacokinetic parameters were estimated by noncompartmental methods. In both study A (oral levofloxacin) and study B (intravenous levofloxacin), steady state was attained within 48 h after the start of the multiple dosing on day 4. Levofloxacin pharmacokinetics were linear and predictable for the single and multiple 500-mg, once-daily oral and intravenous dosing regimens, and the values of the pharmacokinetic parameters for the oral and intravenous administrations were similar. Study C indicated that levofloxacin was rapidly and completely absorbed from the oral tablets, with mean times to the maximum concentration of drug in serum of approximately 1.5 h and mean absolute bioavailability of > or =99%. These results support the interchangeability of the oral and intravenous routes of levofloxacin administration.

It is generally assumed that the systems involved in the transport of organic cations and organic anions in the renal proximal tubule are substrate selective (i.e., organic anions do not inhibit organic cation transport and vice versa). However, recent data obtained in vitro have suggested that the organic anion probenecid inhibits the renal transport of the organic cation cimetidine. We addressed the question of whether this interaction is biologically relevant in human beings. The study involved a two-treatment, randomized crossover design. Six healthy male subjects were given an intravenous infusion of 300 mg cimetidine alone as one treatment and, as the other treatment, received multiple oral doses of probenecid before receiving the cimetidine infusion. The renal clearance of cimetidine and inulin was determined in each period. There were no significant differences between treatments in cimetidine plasma concentrations, apparent volume of distribution, systemic clearance, half-life, amount of drug excreted unchanged in the urine, or nonrenal clearance. Probenecid significantly decreased the renal clearance of cimetidine by decreasing both the filtration clearance and the net secretory clearance. These effects were most evident in the first 1/2 to 1 hour after cimetidine administration, when probenecid levels in plasma and renal tissue would have been the highest. Because there was no effect of probenecid on cimetidine plasma concentrations, this interaction is not clinically relevant to the therapeutic use of these two compounds. However, the study demonstrates that renal interactions between organic cations and organic anions can occur in human beings. The mechanism of this interaction and the implications to other drug combinations are being explored.

Experiments were conducted to study the transport of the histamine H2-receptor antagonist, cimetidine, in luminal membrane vesicles prepared from rabbit renal cortex. Cimetidine accumulated in the vesicles with time. Cimetidine uptake was sensitive to changes in vesicle size, suggesting that the compound is transported into an osmotically reactive intravesicular space. Its rate of uptake could be described by both a saturable and a nonsaturable process. The Km was 4.6 +/- 4.0 microM and the Vmax was 6.8 +/- 2.3 pmol X s-1 X mg protein-1 (mean +/- SD, n = 4). N1-methylnicotinamide (NMN), cimetidine, cimetidine sulfoxide, and ranitidine inhibited the uptake of cimetidine. Cimetidine uptake in the presence of an outwardly directed proton gradient was enhanced in vesicles preloaded with a higher concentration of unlabeled cimetidine (2.4 X 10(-4) M). An outwardly directed proton gradient enhanced the uptake of cimetidine to values exceeding its equilibrium accumulation. Uptake stimulated in this way could be inhibited by the cation, NMN, the bases, ranitidine, and cimetidine sulfoxide, and interestingly, by the anion, probenecid. The effect of probenecid did not appear to be due to nonspecific effects on membrane binding, membrane potential, or vesicle size. These data are consistent with data obtained in isolated perfused proximal tubules, demonstrating that probenecid inhibits cimetidine transport. The data in this study suggest that the effect of probenecid on cimetidine transport specifically involves the transporter in the luminal membrane.

It is generally assumed that the organic cation transport system in the renal proximal tubule is specific for organic cations and the transport of organic cations is not affected by organic anions. However, there are also data in the literature demonstrating that probenecid, a classical inhibitor of organic anion transport systems, inhibits the transport of an organic cation, cimetidine, in the renal proximal tubule. In this study we investigated the effects of probenecid and furosemide on the transport of N'-methylnicotinamide (NMN) the classical substrate of the organic cation transporter, in brush-border membrane vesicles prepared from rabbit renal cortex. In the presence of a pH gradient, both probenecid (10 mM) and furosemide reduced the initial uptake of NMN. Probenecid reduced the initial uptake of NMN to 12.1% of the control values (1.19 +/- 0.26 pmol/mg) and furosemide reduced the initial uptake of NMN to 39.2%. Probenecid (10 mM) also decreased the initial transport of NMN in the absence of a pH gradient. Inhibition of the transport of NMN by probenecid was concentration dependent, with the concentration of probenecid resulting in 50% inhibition of the transport of NMN equal to 2.31 +/- 1.18 mM in the presence of a pH gradient. Probenecid appeared to be a competitive inhibitor of NMN transport. The apparent Km (mean +/- SE) of NMN transport (2.01 +/- 0.78 mM) was increased to 18.7 +/- 10 mM (P less than 0.05) by probenecid (10 mM), whereas the Vmax was not changed (125 +/- 19.2 pmol.s-1.mg-1 vs. 186 +/- 94 pmol.s-1.mg-1, P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)