伊立替康及其主要活性代谢产物在人血浆和唾液中的药物浓度及药动学

The pharmacokinetics and drug concentrations of irinotecan and its active metabolites in human plasma and saliva

目的:测定伊立替康(CPT-11)及其主要活性代谢物SN-38和SN-38G在人血浆和唾液中的浓度,研究伊立替康及其主要活性代谢物在2种体液中药动学参数的差异。方法:6例采用Folfiri两周方案治疗的晚期结肠癌患者,给药剂量180 mg.m-2,测定血浆和唾液中药物浓度,计算药动学参数。样品先经甲醇-乙腈(50∶50)沉淀蛋白,用盐酸酸化使内酯环开环,再定量。采用Waters Platform ZMD4000液相色谱仪,Xterra RP18柱,波长为370 nm,检测波长为470 nm和534 nm。喜树碱作内标。结果:血浆和唾液CPT-11及其活性代谢物,酸性提取物在此条件下的稳定性较好。3种待测物线性范围皆为1～1 000 ng.mL-1,检测限都是1 ng.mL-1。RSD为3.1%～11.7%,测定回收率为93.2%～109.8%,中位提取回收率为91%。CPT-11在2种体液中AUC相近,药动学参数相近;SN-38唾液中的AUC约为血浆的42%;SN-38G在唾液中未检出。结论:建立的方法可用于测定CPT-11,SN-38和SN-38G在人血浆和唾液中的药物浓度,可满足临床进行CPT-11及其主要活性代谢物人体药代动力学研究。在血浆样品不易得时,可采集唾液样品,两者药动学参数具有一定的相关性。

OBJECTIVE To determine the concentration of anti-cancer drug irinotecan （CPT-11 ） and its major active metab olite SN 38,SN-38G in plasma and saliva, and study the difference of pharmacokinetic parameters in the two kinds of humors. METHODS Six cases of advanced colon cancer patients adopted Folfiri two weeks treatment scheme,were given with irinotecan at the dose of 180mg·m -2 ;the drug concentrations in plasma and saliva were determined for calculating the pharmacokinetic parameters. The protein of samples were precipitated by methanol acetonitrile （50：50）, and using hydrochloric acid to open the lactone ring, then quantitated. Waters platform ZMD 4 000 liquid chromatograph, Xterra RP18 column were employed; excita tion wavelength was 370 nm, detection wavelength was 470 nm and 534 nm and taking camptothecin as the internal standard. RESULTS CPT-11, its plasma and saliva active metabolites and the acid extract were stabile under this condition. The linear range of the three analytes was 1 - 1 000 ngomL -1 detection limit was 1 ng·mL-1. The relative standard deviation was 3. 1 - 11.7%, the recovery of determination was 93.2 to 109. 8%. The median extraction recovery was 91 %. AUC of CPT-I 1was similar in both body fluids, the pharmacokinetic parameters were similar; the AUC of SN-38 in saliva was approximately 420/oo of the plasma; SN-38G was not detected in saliva. CONCLUSION The established method could be used for the determination of CPT-11 ,SN-38 and SN-38G concentration in human plasma and saliva, satisfied the conditions of clinical human pharmacoki netic study on CPT-11 and its maior active metabolite. When plasma samples are not easy to collect, saliva samples can be in stead of, both pharmacokinetic parameters are correlation.