Pharmacokinetic Study Of Paracetamol, Caffeine And Aspirin Capsules And Zolmitriptan Orally Disintegrating Tablets

Objective:To develop an HPLC method for simultaneous determination of paracetamol, salicylic acid and caffeine in human plasma and apply it to the pharmacokinetic study of paracetamol, caffeine and aspirin capsules, and to develop a high performance liquid chromatography-tandem mass spectrometry method for the determination and pharmacokinetic study of zolmitriptan orally disintegrating tablets in human plasma.Method:After a liquid-liquid extraction process with ethyl acetate of 400μL plasma, paracetamol, salicylic acid, caffeine and theophylline (internal standard) were separated on an Phenyl(KromasiDcolumn with isocratic elution at a flow-rate of 1.0 mL·min-1.The mobile phase was methanol-tetrahydrofuran-10 mmol·L-1 ammonium acetate buffer containing 0.1% acetic acid (23:2:77,v/v/v) and the UV detector was set at 237 nm. Zolmitriptan plasma samples were prepared by liquid-liquid extraction with diethyl ether-dichloromethane (2:1,v/v) of 500μL plasma, separated on Ultimate XB-C8 column with isocratic elution. The mobile phase was a mixture of acetonitrile and water (containing 5 mmol·L-1 ammonium acetate) (70:30, v/v) at a flow-rate of 0.40 mL·min-1.Multiple reaction monitoring (MRM) using the precursorâ†'product ion combination of m/z 288.0â†'m/z 57.4, and m/z 256.0â†'m/z 166.8 was employed to quantify zolmitriptan and diphenhydramine (internal standard), respectively.Result:The linear calibration curves were obtained over the concentration range of 0.203～16.2μg·mL-1 for paracetamol,0.503～80.4μg·mL-1 for salicylic acid and 0.103～8.24μg·mL-1 for caffeine in human plasma. The intra-and inter-day precision values (RSD) were not more 7.9% and the accuracy (RE) was -9.2%～1.9% at all three QC levels. The main parameters of paracetamol, salicylic acid, caffeine after an oral dose of paracetamol, caffeine and aspirin capsules to 20 healthy volunteers were as follows:Cmax was found to be 4.685±0.728μg·mL-1, 62.83±8.06μg·mL-1 and 2.112±0.407μg·mL-1, Tmax observed was 1.01±0.24 h,2.23±0.70 h and 0.93±0.32 h,the value t1/2 was 2.65±0.78 h,3.02±1.01 h and 4.87±1.89 h, AUC0-t obtained were 16.18±4.10μg·h·mL-1,371.3±85.5μg·h·mL-1 and 13.39±6.22μg·h·mL-1,AUC0-∞obtained were 17.34±4.20μg·h·mL-1,379.5±87.5μg·h·mL-1 and 14.95±6.87μg·h·mL-1,respectively. The standard calibration curves for zolmitriptan were linear in the concentration range of 0.200～20.0 ng·mL-1 in human plasma. The intra-and inter-day precision values (RSD) were not above 14% and the accuracy (RE) was -5.3%～1.0% at all three QC levels. The main pharmacokinetic parameters obtained after an oral dose of 5 mg zolmitritan in orally disintegrating tablets to 18 healthy volunteers were 10.69±4.41 ng·mL-1 for Cmax,2.92±1.65 h for Tmax,4.40±1.64 h for t1/2, 60.08±26.46 ng·h·mL-1 for A UC0-t and 62.55±27.00 ng·h·mL-1 for AUC0-∞, respectively.Conclusion:The methods are proved to be of high specificity, sensitivity, speed and have been successfully utilized for the evaluation of the pharmacokinetics of paracetamol, caffeine and aspirin capsules and zolmitriptan orally disintegrating tablets.