Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients.

PURPOSE: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment. METHODS: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations. RESULTS: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (+/-SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 +/- 0.17 (range, 0.89-1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S-mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 microM (11% inhibition) and 900 microM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200-400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy CONCLUSIONS: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19-mediated minor metabolic pathway of PHT.

Lack of effect of a high-fat meal on the bioavailability of 17 beta-estradiol/norgestimate in healthy postmenopausal women.

The effect of a high-fat meal on the absorption and pharmacokinetics of 17 beta-estradiol (E2), estrone (E1), estrone sulfate (E1S), and 17-deacetylnorgestimate (17d-NGM) were determined in this two-way complete crossover study of a single dose of E2/NGM (2 mg/180 micrograms) in 24 postmenopausal women. Equal numbers of subjects were randomly assigned to two treatment sequences indicated by the order of fed and fasting treatments. Serial blood samples were collected before and after dosing and assayed using validated methods. Food had no effect on the pharmacokinetics of E2, the pharmacologically active estrogen species. Food increased the rates of formation of E1 and E1S and slowed the formation of 17d-NGM. However, because E1 and E1S are pharmacologically less active metabolites of E2, and since the pharmacokinetic alterations in 17d-NGM were observed over a short time period, these results are probably of no clinical relevance. The extent of formation of all analytes, as measured by AUC, was not affected by food. In conclusion, administration of a tablet containing 17 beta-estradiol/norgestimate (2 mg/180 micrograms) was safe and well tolerated by healthy postmenopausal women and may be given without regard to the timing of meals in relation to dosing.

A capillary gas chromatographic assay with nitrogen phosphorus detection for the quantification of topiramate in human plasma, urine and whole blood.

An accurate and robust method involving liquid liquid extraction and capillary gas chromatographic (GC) assay with nitrogen phosphorus detection (NPD) was developed and validated for the quantitative determination of topiramate [2,3:4,5-bis-O-(-1-methylethylidene)-beta-D-fructopyranose sulfamate], Topamax, an anticonvulsant drug, in human plasma, urine, and whole blood. The galactopyranose analog of topiramate was used as the internal standard. A DB-5, fused silica capillary column (J&W Scientific, Folsom, CA) was used, yielding typical retention times of 4.95 min for topiramate and 5.32 min for the internal standard in human plasma. The assay involved organic extraction with methyl t-butyl ether (MTBE) from base, a back extraction into acid and a second extraction in MTBE. The organic solvent was evaporated, and the residue was redissolved and injected for analysis. The standard curve was validated from 0.5 to 50 microg/ml(-1) for human plasma and whole blood, and from 1.0 to 50 microg/ml(-1) for urine. Peak area ratios of drug to internal standard were determined and used to construct a standard curve. The resulting chromatograms showed no endogenous interfering peaks with the respective blank human fluids. Chromatograms corresponding to topiramate and the internal standard produced sharp peaks that were well resolved. This assay showed precision and accuracy of < or = 5%. Two minor human metabolites of topiramate did not interfere with the assay. This assay was successfully applied to determine the pharmacokinetics of topiramate during the development of this drug.

Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses.

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.

Absence of a pharmacokinetic interaction between intravenous theophylline and orally administered levofloxacin.

A randomized, placebo-controlled, two-way crossover study in 16 healthy men was performed to determine the effect of orally administered levofloxacin at steady-state conditions, given at 500 mg every 12 hours, on the pharmacokinetics of theophylline given as a single 4.5-mg/kg intravenous infusion. Participants were assigned randomly to receive theophylline with levofloxacin in one study period and theophylline with placebo in the other period. Fourteen individuals completed the study. Mean (+/-SD) values for theophylline pharmacokinetic parameters for the levofloxacin and placebo treatments, respectively, were peak plasma concentrations (Cmax) of 11.4 (1.8) micrograms/mL and 10.7 (1.3) micrograms/mL; areas under the concentration time curve from time 0 extrapolated to infinity (AUCzero-infinity) of 124 (32) micrograms.hr/mL and 126 (30) micrograms.hr/mL; volumes of distribution at steady state (Vdss) 31.7 (3.5) L and 32.0 (3.9) L; clearances (Cl) of 48.6 (11.6) mL/min and 47.4 (10.3) mL/min; and half-lives (t1/2) of 8.1 (1.9) hours and 8.2 (1.8) hours. There were no statistically significant differences between treatments for any of these parameters. There was no pharmacokinetic interaction between levofloxacin administered orally at steady-state conditions and intravenously administered theophylline.

Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug.

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.

Incremental dosage of the new antipsychotic mazapertine induces tolerance to cardiovascular and cognitive effects in healthy men.

OBJECTIVES: Mazapertine is a structurally novel antipsychotic compound with high affinity for D2, D3, 5-HT1a, and alpha 1 receptors. The objectives were to determine whether tolerance to orthostatic hypotension caused by this compound could be induced by slowly increasing the dose administered and to investigate its effect on cognitive and motor functions. METHODS: Thirteen healthy male subjects received incremental oral doses of mazapertine (from 5 to 50 mg over 7 days; n = 10) or placebo (n = 3) in part I and single doses in parts II (20 or 30 mg or placebo) and III (40 mg or placebo) in a double-blind fashion. Blood pressure, heart rate, cardiac hemodynamics, cognitive functions, and occurrence of acute extrapyramidal symptoms were investigated. RESULTS: Mazapertine appears to be safe and well tolerated when administered orally for 7 days to normal healthy men. No accumulation of serum prolactin occurred after multiple dosing, suggesting limited potential for inducing galactorrhea. The drug was rapidly absorbed, and kinetics appeared to be dose dependent, without accumulation. The elimination half-life was about 5 to 10 hours. No evidence of any positive or negative cognitive effects could be detected. Mild motor symptoms were observed only at high doses (not statistically significant). Mazapertine had a minimal effect on cardiac output and stroke volume. Tolerance to hypotension could be induced by slowly increasing the dose administered. CONCLUSIONS: Mazapertine is well tolerated when administered orally for seven days, and tolerance to hypotension can be induced by slowly increasing the dose administered. Therefore, nothing precludes further clinical testing on patients with schizophrenia.

The effect of probenecid on the renal elimination of cimetidine.

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.

Renal transport of drugs: an overview of methodology with application to cimetidine.

The development of new methods to study transport processes in renal epithelia has greatly enhanced our knowledge of the mechanisms involved in the transport of a number of endogenous compounds. More recently, these methods have been applied to study mechanisms of specific drug transport. This article is intended to provide an overview of the various methods used to study renal elimination of compounds. References to more detailed reviews of the individual methods are provided. Studies of the renal transport of cimetidine, a histamine H2-receptor antagonist, are presented to illustrate the application of these methods to the study of specific drugs. Methods such as clearance techniques and the Sperber chicken preparation used to study renal elimination of compounds in whole animals are briefly described. Techniques to identify the site of renal transport including stop flow, isolated perfused tubules, and micropuncture methods are discussed and references to more technical reviews are cited. The more recently developed methods of isolated membrane vesicles for studying transport across the individual polar membranes of the proximal tubule are discussed along with the relevant studies of the use of these membranes in elucidating the mechanisms involved in the renal transport of cimetidine. Finally, the use of cultured renal epithelial cell lines in studying renal transport is described. Knowledge of drug transport mechanisms in the kidney is important both in drug targeting to the kidney and in understanding the pharmacokinetics of renally eliminated drugs. As exemplified by the studies with cimetidine, only by combining the data from experiments using diverse methodology can the mechanisms involved in the renal excretion of compounds be delineated.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions of organic anions with the organic cation transporter in renal BBMV.

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)

Cimetidine transport in isolated luminal membrane vesicles from rabbit kidney.

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.

Saliva, urine and plasma analysis of dyphylline via HPLC.

Improved assay methods for determination of dyphylline levels in plasma, saliva, and urine utilizing high pressure liquid chromatography have been developed. Detection of levels as low as 25 ng/ml from 0.5 ml plasma and 50 ng/ml from 0.5 ml saliva were possible. Both procedures utilized the same extraction process. A separate extraction process was used for dyphylline analysis in urine due to the presence of interferring substances occurring with previous methods. The method was applied to samples of one subjects plasma, saliva and urine after administration of dyphylline.