Guemei A A, Cottrell J, Band R, Hehman H, Prudhomme M, Pavlov M V, Grem J L, Ismail A S, Bowen D, Taylor R E, Takimoto C H
Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20889, USA.
Cancer Chemother Pharmacol. 2001 Apr;47(4):283-90. doi: 10.1007/s002800000258.
To characterize the relationships between human plasma irinotecan carboxylesterase-converting enzyme activity, caboxylesterase-mediated hydrolysis of p-nitrophenyl acetate (pNPA), and the butyrylcholinesterase-mediated hydrolysis of butyrylthiocholine in human plasma and to test the ability of these in vitro tests to predict the variability in SN-38 pharmacokinetics in adult patients during a prolonged infusion of irinotecan.
Individual plasma-converting enzyme activity was measured in 20 adult cancer patients participating in a pharmacokinetic and phase I clinical trial of a prolonged 96-h intravenous infusion of irinotecan. The pNPA and butyrylthiocholine hydrolysis in patient plasma was also assayed.
The irinotecan carboxylesterase-converting enzyme in human plasma had a Vmax of 89.9 +/- 22.7 pmol/h per ml plasma and a Km of 207 +/- 56 microM (mean +/- SD, n = 3). The mean value of the specific activity of this enzyme in 20 adult cancer patients was 10.08 +/- 2.96 pmol/h per ml plasma ranging from 5.43 to 15.39 pmol/h per ml. The area-under-the-concentration-versus time curve (AUC) ratio of SN-38 to irinotecan (AUCSN-38/AUCCPT-11) was used to assess the relative SN-38 exposure to the active metabolite in individual patients. Pharmacokinetic variations in the relative exposure to SN-38 did not correlate with the measured carboxylesterase-converting enzyme activity nor with plasma butyrylcholinesterase activity in our patient population. However, it did correlate with the measured pNPA hydrolysis activity in patient plasma (r2 = 0.350, P = 0.0124, n = 18).
Determination of patient plasma pNPA hydrolysis activity may have utility in predicting SN-38 pharmacokinetics during prolonged infusions of irinotecan.
描述人血浆中伊立替康羧酸酯酶转化酶活性、羧酸酯酶介导的对硝基苯乙酸（pNPA）水解以及丁酰胆碱酯酶介导的丁酰硫代胆碱在人血浆中水解之间的关系，并测试这些体外试验预测成年患者在长时间输注伊立替康期间SN-38药代动力学变异性的能力。
在20名参与伊立替康96小时静脉延长输注药代动力学和I期临床试验的成年癌症患者中测量个体血浆转化酶活性。还测定了患者血浆中pNPA和丁酰硫代胆碱的水解情况。
人血浆中的伊立替康羧酸酯酶转化酶Vmax为每毫升血浆89.9±22.7 pmol/h，Km为207±56 μM（平均值±标准差，n = 3）。该酶在20名成年癌症患者中的比活性平均值为每毫升血浆10.08±2.96 pmol/h，范围为每毫升血浆5.43至15.39 pmol/h。用SN-38与伊立替康的浓度-时间曲线下面积比（AUCSN-38/AUCCPT-11）评估个体患者中SN-38相对于活性代谢物的暴露情况。在我们的患者群体中，SN-38相对暴露的药代动力学变化与测得的羧酸酯酶转化酶活性和血浆丁酰胆碱酯酶活性均无相关性。然而，它与患者血浆中测得的pNPA水解活性相关（r2 = 0.350，P = 0.0124，n = 18）。
测定患者血浆pNPA水解活性可能有助于预测伊立替康长时间输注期间的SN-38药代动力学。
