Résumé
OBJECTIVE To investigate the effects of omeprazole on pharmacokinetic parameters of imatinib in rats. METHODS According to body weight， the rats were divided into imatinib+low-dose， medium-dose， and high-dose omeprazole groups， imatinib group， with 6 rats in each group. They were given omeprazole suspension at the doses of 1.8， 3.6 and 7.2 g/kg， or 0.5% sodium carboxymethyl cellulose solution intragastrically respectively； one hour later， imatinib suspension was administered by oral gavage at a the dose of 10 mg/kg. Blood sample （100 μL） was taken from the orbit before and 0.5， 1， 2， 2.5， 3， 4， 5， 6， 8， 12， 24 and 36 hours after intragastric administration of imatinib. Using imatinib-d3 as internal standard， the plasma concentrations of imatinib and its metabolite N-desmethyl imatinib in rat were determined by high performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were calculated by DAS 2.0 software and compared. RESULTS Compared with imatinib group， AUC0－∞ and AUMC0－∞ of imatinib in rat plasma of imatinib+medium-dose omeprazole group， cmax， t1/2， AUC0－∞ and AUMC0－∞ of imatinib in rat plasma of imatinib+high-dose omeprazole group were all increased or prolonged significantly （P＜0.05）. Compared with imatinib group， AUC0－∞ and AUMC0－∞ of N-desmethyl imatinib in rat plasma of imatinib+medium-dose omeprazole group， and cmax and AUC0→∞ of N-desmethyl imatinib in rat plasma of imatinib+high-dose omeprazole group were decreased significantly （P＜0.05）. CONCLUSIONS Omeprazole may increase the plasma concentration of imatinib in rats and reduce the plasma concentration of N-desmethyl imatinib in rats， which may be associated with inhibiting the metabolism of imatinib.
Résumé
OBJECTIVE To establish a method for the determination of plasma protein binding rate of imatinib and its metabolite（N-desmethyl imatinib ）and apply it to patients with gastrointestinal stromal tumor （GIST）.METHODS Using imatinib - d8 as the internal standard ，after being deproteinized methanol ，the sample was determined by equilibrium dialysis combined with liquid chromatography -tandem mass spectrometry . The free concentrations of imatinib and its metabolites in plasma of GIST patients were detected by the same method . RESULTS The protein binding rates of imatinib with albumin ，α1-acid glycoprotein and globulin at 120 ng/mL and 4 000 ng/mL were （92.5±1.0）% and（91.7±0.4）%，（56.6±2.0）% and（62.6±2.6）%，（56.3±3.1）% and （68.0±8.6）% ，respectively. The protein binding rates of N-desmethyl imatinib with albumin ，α1-acid glycoprotein and globulin at 60 ng/mL and 2 000 ng/mL were （90.6±3.5）% and（91.3±1.5）%，（54.1±5.1）% and（63.7±1.3）%，（56.2±7.6）% and（67.5±7.3）%，respectively. Compared with the low concentration group of imatinib （120 ng/mL）and its metabolite （60 ng/mL），the plasma protein binding rate of high concentration of imatinib （4 000 ng/mL）and its metabolite （2 000 ng/mL）with α1-acid glycoprotein and globulin was significantly increased （P＜ Δ基金项目 国家自然科学基金资助项目（No.81503160）；江苏省 0.05），but there was no signifi -cant difference with albumin 卫生健康发展研究中心 2021年度开放课题（No.JSHD2021004）；江苏 （P＞0.05）. In blank plasma ，the protein binding rates of imatinib（4 000 ng/mL）at high concentration and its metabolites（2 000 ng/mL）were significantly lower than those of low （120， 60 ng/mL） and medium （750， 375 ng/mL）concentration （P＜0.01）. Average protein binding rates of imatinib and its metabolite in plasma of GIST patients were （99.0±0.3）% and（99.2±0.3）%，respectively；the correlation coefficients between the concentrations of imatinib and its metabolites and the protein binding rates were －0.298 5 and －3.332 3，respectively（all P＜0.05）. CONCLUSIONS The method for determining the plasma protein binding rates of imatinib and its metabolites is successfully established . The plasma protein binding rates of imatinib and its metabolites in patients with GIST are negatively correlated with drug concentration .