The pharmacokinetics of orally administered fudosteine in healthy Chinese volunteers

Abstract

The pharmacokinetics of fudosteine in healthy Chinese volunteers was investigated for the first time after single- and multiple-dose administration. Five male and five female volunteers were enrolled in this study. Each subject received 400 mg fudosteine capsules (the therapeutic dose) on day 1 after overnight fasting for the single-dose study and three times daily oral administration (400 mg) for 5 consecutive days until the sixth morning for the multiple-dose study. Serial blood samples were collected at specified time intervals up to 16 hours following the first and last doses of fudosteine. Plasma harvested from the blood was separated and analyzed for fudosteine levels by a validated high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC/ESI/MS) method employing percolumn derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl). Noncompartmental analysis was used for the calculation of the total area under the plasma concentration-time curve (AUC) from time zero to time infinity and the terminal half-life (t1/2) of fudosteine. The pharmacokinetic parameters for single- and multiple-dose administration were estimated as follows: Cmax amounted to 10.13+/-4.39 microg/mL and 11.75+/-6.51 microg/mL, tmax to 0.69+/-0.36 h and 0.53+/-0.12 h and t1/2 to 2.33+/-0.63 h and 2.40+/-0.37 h, respectively. No significant differences were found between single- and multiple-dose oral administration, although gender differences were observed.

High-throughput determination of fudosteine in human plasma by liquid chromatography–tandem mass spectrometry, following protein precipitation in the 96-well plate format

“…The concentration-time data were analyzed by non-compartmental method and the mean values of pharmacokinetic parameters are C max 6.39 ± 2.67 g mL −1 , T max 0.42 ± 0.18 h, t 1/2 3.89 ± 0.65 h, MRT 4.55 ± 0.74 h, AUC 0-12 14.10 ± 4.88 g h mL −1 , AUC 0-∞ 15.40 ± 5.13 g h mL −1 . Jiao et al [5] and Ding et al [3] reported the pharmacokinetic studies of fudosteine in 10 and 12 healthy Chinese volunteers after single-dose administration of 400 mg, with an even proportion of both sexes, respectively. The mean AUC observed in Jiao's study [5] is 23.95 g h mL −1 and in Ding's study [3] 29.00 g h mL −1 .…”

“…Jiao et al [5] and Ding et al [3] reported the pharmacokinetic studies of fudosteine in 10 and 12 healthy Chinese volunteers after single-dose administration of 400 mg, with an even proportion of both sexes, respectively. The mean AUC observed in Jiao's study [5] is 23.95 g h mL −1 and in Ding's study [3] 29.00 g h mL −1 . In our study on ten healthy male volunteers, the mean AUC is 15.40 g h mL −1 , about 45% lower than Jiao's and Ding's.…”

“…Because fudosteine has little retention on the ODS column and lacks UV absorption and fluorescent functional groups, several methods require prior derivatization of fudosteine to achieve a suitable chromatographic behavior and detection sensitivity such as high performance liquid chromatography with fluorescence detection [3] and liquid chromatography-electrospray ionization mass spectrometry [4,5]. These two methods suffered from a complicated and time-consuming derivatization procedure and long chromatographic run time to elimination possible endogenous interference, which do not meet high-throughput analysis needs with respect to an efficient extraction procedure with small size plasma, reduced analysis time and high sensitivity when a large number of samples for quantification.…”

Pharmacokinetics and Bioequivalence of Fudosteine in Healthy Chinese Volunteers Under Fasting and Fed Conditions: A 4‐Way Replicate Crossover Study

“…3 Fudosteine, (-)-(R)-2-amino-3-((3-hydroxypropyl) thio) propionic acid (SS320A) (Figure 1), is a cysteine derivative that was approved in Japan in 2001 as a mucoactive agent for the treatment of chronic respiratory diseases, such as bronchial asthma, chronic bronchitis, pulmonary emphysema, and so on. 4 The multiple pharmacological effects of fudosteine on…”

“…Its metabolites (M1-M4) are shown in Figures 1, and M1 and M3 are the major metabolites. 9,10 This study aimed to evaluate the bioequivalence between generic and brand-named fudosteine under fasting and fed conditions and the effects of food on the PK parameters of these 2 drugs in heathy Chinese volunteers. Subjects.…”