Gas chromatography nitrogen phosphorous detection (GC-NPD) assay of tofisopam in human plasma for pharmacokinetic evaluation.

Tofisopam (1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) has been shown to be an effective anxiolytic agent in the wide-ranging clinical practice. A high sensitive gas chromatography nitrogen phosphorous detection (GC-NPD) bioanalytical method was developed and validated for the purpose of pharmacokinetic study of tofisopam. A liquid-liquid extraction method was used for the sample preparation. The mean recovery for tofisopam was 69.8% and the inter- and intra-day precision values were well below the 15% limit established for bioanalytical methods. A similar compound, girizopam was used as internal standard. The assay was linear in the 5-500 ng/ml range corresponding to therapeutically relevant plasma levels. The concentrations of the compound were measured in the plasma samples of 12 healthy male volunteers and the pharmacokinetic parameters were determined from the plasma concentration-time data. A rapid absorption and distribution, relatively short biological half-life and considerable inter-individual variation in the plasma concentration levels of parent compound were the main characteristics of the pharmacokinetics of tofisopam. According to these results, the new (GC-NPD) bioanalytical method proved to be capable of measuring concentration of tofisopam in human plasma and was successfully applied in a single dose pharmacokinetic study.

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.