Simultaneous determination of sarpogrelate and its active metabolite in human plasma by liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study

Abstract

We established a rapid and simple liquid chromatography with tandem mass spectrometry method for the simultaneous determination of sarpogrelate and its active metabolite, M-1, in human plasma. Sarpogrelate, M-1, and the internal standard, ketanserin, were extracted from a 50 μL aliquot of human plasma by protein precipitation using acetonitrile. Chromatographic separation was performed on a Shim-pack GIS ODS C18 column (100 × 3.0 mm; 3 μm) with an isocratic mobile phase consisting of 10 mM ammonium acetate and acetonitrile (70:30, v/v) at a flow rate of 0.6 mL/min; the total run time was <2.5 min. Mass spectrometric detection was conducted in selected reaction-monitoring mode with positive electrospray ionization at m/z 430.35 → 135.10 for sarpogrelate, m/z 330.30 → 58.10 for M-1, and m/z 395.70 → 188.85 for ketanserin. The linear ranges of concentration for sarpogrelate and M-1 were 1-1000 and 0.5-500 ng/mL, respectively. The coefficient of variation for the assay's precision was ≤9.95%, and the accuracy was 90.6-107%. All analytes were stable under various storage and handling conditions, and no relevant crosstalk and matrix effect was observed. This method was successfully applied to a pharmacokinetic study after oral administration of a 100 mg sarpogrelate tablet to healthy male Korean volunteers.

Simultaneous determination of β-sitosterol, campesterol, and stigmasterol in rat plasma by using LC-APCI-MS/MS: Application in a pharmacokinetic study of a titrated extract of the unsaponifiable fraction ofZea mays L.

“…In this study, 48 incurred samples were reanalyzed in a separate batch run. The difference was calculated with the following equation: [(reanalyzed value–initial value)/average of the two] × 100%] . The results showed that 89.6, 93.8, and 87.5% of ISR samples met the accepted criteria (within 20%) for β‐sitosterol, campesterol, and stigmasterol, respectively, indicating good reproducibility of the present method.…”

Application of physiologically based pharmacokinetic modeling in predicting drug&ndash;drug interactions for sarpogrelate hydrochloride in humans

“…The LC-MS/MS conditions for the determination of sarpogrelate and M-1 were the same as previously described. 20 The metabolic stability expressed as a percentage of the test compound (sarpogrelate or M-1) remaining was calculated by comparing the peak area ratios of sarpogrelate and M-1 to the internal standard at specific time points relative to time 0 minutes. The t 1/2 was estimated from the slope of the initial linear range of the logarithmic curve of the residual sarpogrelate (%) versus time, assuming a first-order kinetics.…”

“…The plasma concentration-time profiles of sarpogrelate and M-1 after a 100-mg oral dose of sarpogrelate obtained from a previously published study were used to build the PBPK model. 20 The PBPK model was evaluated by comparing the predicted pharmacokinetics profiles of sarpogrelate and M-1 with the observed published data. 20 – 24 , 41 – 43 Then, the predicted pharmacokinetic parameters such as AUC, C max , and time to achieve C max ( T max ) were calculated to compare with reported clinical data.…”

“…The highest mean C max of sarpogrelate observed in clinical trials was 1.7 μM after a single 100 mg dose of sarpogrelate hydrochloride. 20 – 24 The reported plasma protein binding of sarpogrelate was approximately 95% 17 and the predicted nonspecific binding to microsomes was 3.1% ( Table 1 ). Using the FDA guidance equation, the resulting R value (1+ [I]/K i ) was 2.45 for CYP2D6.…”

Bioequivalence of Sarpogrelate in Healthy Chinese Subjects Under Fasting and Fed Conditions: A 4‐Way Replicate Crossover Investigation by a Reference‐Scaled Average Bioequivalence Approach

“…In a previous study of the oral administration of sarpogrelate (100 mg) under fasting conditions, the maximum drug concentration (C max ) reached approximately 650 ng/mL at 0.67 hour, and the area under the curve (AUC) was about 690 h·ng/mL . In humans, it has been shown that sarpogrelate is quickly hydrolyzed to M‐1 and eliminated from plasma (half‐life of drug excretion in the terminal phase [t 1/2 ] ≈ 0.7 hour), which is faster than the duration of its pharmacological effects.…”