Pharmacokinetics Study Of Mitiglinide Tablets In Healthy Volunteers By HPLC-MS/MS

ObjectiveSo to reveal the course of absorption,distribution,metabolism and excretion of drug in body have become the focal point of clinical pharmacokinetics study.This is a ingredient of comprehensive understanding interaction between human and drugs,is basis for making a clinical reasonable plan of drug used.Because of the low drug concentration and the complex composition in biological samples,it is of great importance to build up suitable quantitatively analysis methods. In this paper quantitatively analysis methods of mitiglinide have been established by use of modern drug analysis apparatus including HPLC-MS/MS.Studies have also been carried out to reveal the pharmacokinetic behaviors of this drug.We could understand axiom of Pharmacoldnetics of mitiglinide in chinese healthy volunteers,and could offer scientific evidence of clinical reasonable used of this drug.MethodsA sensitive,specific,accurate and precise method of HPLC- MS/MS has been developed to determine mitiglinide in human plasma.Plasma samples were added nateglinide(internal standard),and pretreated by direct abstraction with aether.The chromatographic separation mitiglinide from human plasma were achieved using UPLCC₁₈,and plasma samples were blowed drying by nitrogen at 40℃.Mass spectrum analysis was carride out by ESI source.The MS response and selectivity in positive ion modes were evaluated.The time of scan was 0.10 s.The[M+ H]⁺ m/z 316.2→m/z 298.2 for mitiglinide and[M+H]⁺ m/z 318.2→m/z 166.0 for nateglinide were selected as detecting ions.Nebulizer gas was nitrogen gas and was set to 400 L·h^-1at a temperature of 350℃.Block temperature was 110℃.The capillary entrance was set to a voltage of 2.50kV and the exit to 20V.CID was set to a voltage of 10eV and 11eV. A single dose 5mg and 10mg mitiglinide tablets was given to 20 healthy volunteers.The pharmacokinetics were measured.ResultsThe recovery of mitiglinide was 75.8～83.7%,and the minimum detection concentration of mitiglinide was 1.08ng·mL^-1.The calibration curves were linear over the concentration range of 1.08～5.4×10³ng.mL^-1for mitiglinide.The RSD values of intra-day and inter-day are lower than 15%.While being refrigerated under-20℃within 21 days,the plasma samples are stable.The main pharmacokinetic of 5mg and 10mg test tablets were as follow:C_max were(570.20±76.37)and(899.75±133.67)ng·mL^-1;t_maxwere(0.51±0.13)and (0.51±0.19)h;AUG_0-6were(839.25±310.80)and(1848.68±441.93)ng·h·mL^-1; AUC_0-∞were(871.98±329.46)and(1957.65±507.04)ng·h·mL^-1;t_1/2were (1.19±0.13)and(1.35±0.26)h;MRT_0.6were(1.59±0.17)and(1.90±0.20)h; MRT_0-∞were(1.80±0.26)and(2.22±0.32)h;CL were(112.15±49.25)and (90.24±22.60)mL·min^-1;VD were(11.43±4.93)and(10.30±1.49)L.ConclusionThe method proves to be a stable and reliable for pharmacokinetic studies of mitiglinide.