目的 測(cè)定連續(xù)給予注射用酒石酸長(zhǎng)春瑞濱膠束的毒動(dòng)學(xué)參數(shù)，并與注射用酒石酸長(zhǎng)春瑞濱進(jìn)行比較。方法 選取16只比格犬隨機(jī)分為4組，雌雄各半，分別連續(xù)iv給予注射用酒石酸長(zhǎng)春瑞濱膠束低、中、高劑量（0.29、0.58、1.174 mg/kg）與注射用酒石酸長(zhǎng)春瑞濱1.174 mg/kg，建立測(cè)定比格犬血漿中酒石酸長(zhǎng)春瑞濱濃度的液相色譜-串聯(lián)質(zhì)譜（LC-MS/MS）法，測(cè)定血藥濃度，采用DAS3.1.4藥動(dòng)學(xué)軟件計(jì)算動(dòng)力學(xué)參數(shù)。結(jié)果 比格犬iv給予注射用酒石酸長(zhǎng)春瑞濱膠束低、中、高3個(gè)劑量，血藥濃度、AUC_（0-t）、C_max隨給藥劑量的增加而增大；連續(xù)iv給藥，低、中、高劑量組動(dòng)物血藥濃度、AUC_（0-t）、C_max在給藥第1、29、71天時(shí)均變化不大，無(wú)明顯蓄積傾向。而注射用長(zhǎng)春瑞濱膠連續(xù)iv給藥后隨給藥時(shí)間延長(zhǎng)，動(dòng)物血藥濃度、AUC_（0-t）、C_max有上升趨勢(shì)，AUC_（0-t）蓄積因子分別為2.08、1.80，C_max蓄積因子分別為2.58、2.32，均有蓄積傾向。結(jié)論 注射用酒石酸長(zhǎng)春瑞濱膠束與普通注射用酒石酸長(zhǎng)春瑞濱毒動(dòng)學(xué)參數(shù)比較，無(wú)明顯的蓄積傾向，可降低長(zhǎng)期服藥的毒性風(fēng)險(xiǎn)。

Objective To establish a quick method to analyze vinorelbine tartrate in plasma of beagle dogs and compare the toxicokinetics of vinorelbine tartrate micelle for injection and vinorelbine tartrate for injection. Methods Sixteen beagle dogs were selected and divided into four groups, who received multiple dose of 0.29, 0.58 and 1.174 mg/kg vinorelbine tartrate micelle for injection and 1.174 mg/kg vinorelbine tartrate for injection respectively. The plasma concentrations of vinorelbine tartrate micelle were determined by LC-MS/MS. Using DAS3.1.4 pharmacokinetic software to calculate the kinetic parameters. Results The blood concentration, AUC_(0-t) and C_max of beagle dogs increased with the increase of iv dose. The blood concentration, AUC_(0-t) and C_max of beagle dogs in the low, middle and high dose groups did not change significantly at the 1st, 29th and 71st day of administration. After iv continuous administration of vinorelbine for injection, the concentration of blood drug, AUC_(0-t), C_max increased with the increase of administration time. The accumulation factors of AUC_(0-t) were 2.08, 1.80, and C_max were 2.58 and 2.32, respectively. Conclusion Compared with the pharmacokinetic parameters of vinorelbine tartrate for injection, vinorelbine tartrate for injection has no obvious accumulation tendency, which can reduce the risk of long-term toxicity.

R969.1

科技部"重大新藥創(chuàng)制"科技重大專項(xiàng)（2015ZX09501004-002-003）