Pharmacokinetics And Bioequivalence Of S-1 Capsules In Chinese Patients With Cancer

To study the pharmacokinetics and bioequivalence of S-1 in Chinese patients with cancer after single oral administration.A single dose of 50 mg test or reference formulation was given according to an open randomized two way crossover design. The plasma concentrations of tegafur (FT), 5-fluorouracil (5-FU), gimeracil (CDHP) and oxonic acid (Oxo) in human plasma were determined by liquid chromatography-tandem mass spectrometry.Using liquid chromatography-tandem mass spectrometry to simultaneously determine FT, 5-FU and CDHP in human plasma after plasma sample precipitated by methanol. Separation was achieved on a Synergi 4μHydro-RP 80? (150×4.6 mm I.D., 4μm) column with the mobile phase consisted of methanol–water–ammonia–acetic acid (27: 73: 0.0018: 0.018, v/v/v/v). A tandem mass spectrometer equipped with electrospray ionization source was used as the detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring (MRM) of the transitions m/z 199→m/z 42 for FT, m/z 129→m/z 42 for 5-FU, m/z 144→m/z 100 for CDHP and m/z 122→m/z 78 for nicotinic acid, respectively.Using liquid chromatography-tandem mass spectrometry to determine Oxo in human plasma. Plasma sample pretreatment involved protein precipitation by methanol, then all supernatants were mixed with 1M HCl. The mixture was then incubated at 60°C for 20 min to accomplish the decarboxylation of oxonic acid. The reaction solution was evaporated to dryness at 40°C under nitrogen. Approximately 10 mg of potassium carbonate and 300μ?L of the derivatization reagent (dissolving 10 mg 4-Bromomethyl-7-methoxycoumarin and 30 mg 18-crown-6 in 10 mL of N,N-dimethylformamide ) were added to the residue. The mixture was left to react for 1 h at 60°C, then 3 mL ethyl acetate were added to the reaction solution to extract derivative products. The organic layer was evaporated to dryness at 40°C under nitrogen, then reconstituted in the mobile phase consisted of 5% acetic acid. Separation was achieved on Zorbax SB-C18 (150×4.6 mm I.D., 5μm) column with the mobile phase consisted of methanol–20mmol/L ammonium acetate–formic acid (70: 30: 0.3,v/v/v). A tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as the detector and operated in the positive ion mode. Quantification was performed using multiple reaction monitoring (MRM) of the transitions m/z 490→m/z 259 for derivative of oxonic acid and m/z 495→m/z 262 for derivative of [13C2,15N3] oxonic acid, respectively.The main pharmacokinetic parameters of test and reference formulation were as follows: the values of Cmax for FT were (1887±491) ng/mL and (1876±522) ng/mL, Tmax were (1.0±0.5) h and (1.0±0.9) h, T1/2 were (11.5±5.3) h and (11.6±5.0) h, AUC0-t were (20764±9612) ng·h/mL and (19763±10077) ng·h/mL, respectively. The values of Cmax for 5-FU were (122±44.3) ng/mL and (120±45.1) ng/mL, Tmax were (2.4±1.2) h and (1.9±0.9) h, T1/2 were (2.2±1.8) h and (2.1±1.6) h, AUC0-t were (591±176) ng·h/mL and (580±187) ng·h/mL, respectively. The values of Cmax for CDHP were (305±107) ng/mL and (297±104) ng/mL, Tmax were (1.4±0.6) h and (1.3±0.6) h, T1/2 were (4.1±1.8) h and (4.0±2.5) h, AUC0-t were (1458±1094) ng·h/mL and (1410±1043) ng·h/mL, respectively. The values of Cmax for Oxo were (77.4±77.3) ng/mL and (79.9±73.4) ng/mL, Tmax were (2.7±2.6) h and (2.3±2.4) h, T1/2 were (4.7±2.7) h and (4.3±2.0) h, AUC0-t were (404±333) ng·h/mL and (428±377) ng·h/mL, respectively.The test and reference formulation had the similar pharmacokinetic characteristics. The relative bioavailability of FT, 5-FU, CDHP and Oxo in test formulation were (108.1±23.6)%, (104.9±24.2)%, (107.2±23.9)% and (103.4±39.0)%, respectively. AUC0-t, AUC0-∞and Cmax were logarithmically transformed, then used analysis of variance, two one-sided t test and 90% confidence interval. Compared with the corresponding parameters for FT in reference formulation, the 90% confidence intervals of AUC0-t, AUC0-∞and Cmax for FT in test formulation were 98.5%-113.9%, 98.3%-114.3% and 92.9%-111.1%, respectively. Compared with the corresponding parameters for 5-FU in reference formulation, the 90% confidence intervals of AUC0-t, AUC0-∞and Cmax for 5-FU in test formulation were 95.0%-111.0%, 95.9%-112.7% and 94.1%-112.9%, respectively. Compared with the corresponding parameters for CDHP in reference formulation, the 90% confidence intervals of AUC0-t, AUC0-∞and Cmax for CDHP in test formulation were 98.5%-112.1%, 99.0%-110.3% and 89.9%-120.9%, respectively. Compared with the corresponding parameters for Oxo in reference formulation, the 90% confidence intervals of AUC0-t, AUC0-∞and Cmax for Oxo in test formulation were 83.3%-112.2%, 84.6%-113.9% and 74.7%-121.6%, respectively. The 90% confidence intervals for the test/reference formulation ratio of AUC were within the acceptable range of 80.0% to 125%. The 90% confidence intervals for the test/reference formulation ratio of Cmax were within the acceptable range of 70.0% to 143%. The results demonstrated that two formulations were bioequivalent and may be used interchangeably.