Gupta E, Wang X, Ramirez J, Ratain M J
Department of Medicine, University of Chicago Medical Center, IL 60637, USA.
Cancer Chemother Pharmacol. 1997;39(5):440-4. doi: 10.1007/s002800050595.
Irinotecan (CPT-11) is hydrolyzed to its active metabolite SN-38 which is subsequently conjugated by uridine diphosphate glucuronosyl transferase (UDP-GT) to the glucuronide (SN-38G). Both preclinical and clinical data indicate that conjugation is a primary clearance mechanism for SN-38 with the plasma glucuronide levels being substantially higher than those of SN-38. This investigation was designed to determine the possibility of modulation of glucuronidation of SN-38 and its effect on the disposition of the parent drug and metabolites.
Female Wistar rats were pretreated with 200 mg/kg valproic acid (VPA), an inhibitor of glucuronidation, 5 min prior to the administration of 20 mg/kg irinotecan. The control rats were given 20 mg/kg irinotecan only. To study the effect of inducers of UDP-GT activity, rats were pretreated with phenobarbital (PB) before irinotecan administration.
Pretreatment with VPA caused a 99% inhibition in the formation of SN-38G leading to a 270% increase in the area under plasma concentration-time curve (AUC) of SN-38 compared with the control rats. The irinotecan estimations were unchanged in the two groups. PB pretreatment caused a 1.7-fold increase in the AUC of SN-38G and a concomitant 31% and 59% reduction in the AUCs of SN-38 and irinotecan, respectively.
The most plausible explanation for the alterations in SN-38G disposition is inhibition of SN-38 conjugation by VPA and induction of the conjugation by PB.
伊立替康（CPT - 11）水解生成其活性代谢产物SN - 38，随后SN - 38由尿苷二磷酸葡萄糖醛酸转移酶（UDP - GT）与葡萄糖醛酸结合生成葡萄糖醛酸化物（SN - 38G）。临床前和临床数据均表明，结合反应是SN - 38的主要清除机制，血浆中葡萄糖醛酸化物水平显著高于SN - 38。本研究旨在确定调节SN - 38葡萄糖醛酸化的可能性及其对母体药物和代谢产物处置的影响。
雌性Wistar大鼠在给予20 mg/kg伊立替康前5分钟，先用200 mg/kg丙戊酸（VPA，一种葡萄糖醛酸化抑制剂）进行预处理。对照大鼠仅给予20 mg/kg伊立替康。为研究UDP - GT活性诱导剂的作用，在给予伊立替康前用苯巴比妥（PB）对大鼠进行预处理。
与对照大鼠相比，VPA预处理导致SN - 38G生成受到99%的抑制，SN - 38血浆浓度 - 时间曲线下面积（AUC）增加270%。两组中伊立替康的测定值未发生变化。PB预处理使SN - 38G的AUC增加1.7倍，同时SN - 38和伊立替康的AUC分别降低31%和59%。
SN - 38G处置改变的最合理原因是VPA抑制了SN - 38的结合反应，而PB诱导了该结合反应。
