| Preclinical pharmacokinetic study is important in evaluating a novel drug, and the basis of the study is a sensitive and selective method with good accuracy and precision. A new LC/MS/MS method for determination of imrecoxib in biological fluids was developed and validated and successfully used in the preclinical pharmacokinetic and toxicokinetic study.1. The development of a LC/MS/MS method for determination of imrecoxib in animal plasmaA highly sensitive and rapid method using reversed-phase liquid chromatography combined with tandem mass spectrometry has been developed for the quantitative analysis of imrecoxib in animal plasma. BAP910, a structurally related analog of imrecoxib, was used as the internal standard. A small volume of plasma (100μL) was processed using liquid-liquid extraction. The extract was chromatographed on a YMC-pack ProC18 column. The mobile phase consisted of acetonitrile-water-formic acid (80: 20: 1, v/v), at a flow rate of 0.6 mL·min-1. A Finnigan TSQ tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor/product ion combinations of m/z 370- 236 (imrecoxib) and m/z 374→236 (internal standard, BAP910) was used to quantify imrecoxib. The assay was reproducible and linear for imrecoxib in the range of 2.0 - 5000.0 ng·mL-1. The lower limit of quantification was 2.0 ng·mL-1. Each sample was chromatographed only 2.5 min. The precision was within 9% and RE value was within the range of \3%, respectively. The extraction recovery was greater than 89%.2. The preclinical pharmacokinetics of imrecoxib studied by LC/MS/MSThe preclinical pharmacokinetics of imrecoxib was systematically studied by the validated LC/MS/MS method.Investigation of imrecoxib absorptionFollowing an oral administration of imrecoxib to rats and dogs in three doses, respectively, the plasma concentrations of imrecoxib were determined by the validated LC/MS/MS method. The pharmacokinetic parameters were assessed by non-compartmental method using TOPFIT. Cmax, AUCo.t andAUCo.x were all dose proportional (r>0.8217, p<0.01) in rats. The concentration in plasma-time curves after an i.v. administration to rats and dogs were all fitted to two-compartment models. Comparison between AUCo.t after an oral administration and an i.v. administration indicated that the average absolute bioavailabilities of imrecoxib in rats and dogs were 37.2% and 23.9%, respectively.There were gender differences in imrecoxib pharmacokinetics in rats. After an oral administration of imrecoxib, there's higher elimination rate in male rats (p<0.05). Estimated AUCo-t values in male and female rats showed that AUCo.t value in female was much higher than that in male (p<0.1). The absolute bioavailabilities of imrecoxib in female and male rats were 41.8% and 31.5%, respectively.. There was no gender difference observed in imrecoxib pharmacokinetics in dogs.Investigation of imrecoxib distributionAfter oral administration of imrecoxib to rats, the elimination rates of imrecoxib in all tissues were relatively fast and the drug was unlikely to accumulate. Relatively high concentration presented in liver and fat showed that imrecoxib was easily metabolized in hepar and accumulated in fatty tissues due to its highly lipophilic character. The lowest concentration existed in brain showed a poor penetration into central nervous system. Within 3 h after i.g. administration, the concentrations in the tissues showed no gender difference, while after 3 hpostdose, concentrations of imrecoxib in some tissues of female were significantly higher than those of male. This indicated that gender difference may exist in distribution and metablism phases rather than absorption phase in rats.Investigation of the plasma protein binding of imrecoxibAt rat plasma concentrations of 400 ng·mL-1, 1000 ng·mL-1 and 4000 ng·mL-1, the plasma protein bindings of imrecoxib were measured 94.4±... |
PDF Full Text Request