Zhou S, Kestell P, Tingle M D, Ching L M, Paxton J W
Department of Pharmacology and Clinical Pharmacology, The University of Auckland School of Medicine, New Zealand.
Cancer Chemother Pharmacol. 2001 Jun;47(6):541-4. doi: 10.1007/s002800100285.
Coadministration of thalidomide, cyproheptadine or diclofenac has been shown to increase the area under the plasma concentration-time curve (AUC) of the novel antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice. The aim of this study was to further investigate these pharmacokinetic DMXAA-drug interactions in the rat model.
The effects of coadministration of L-thalidomide, cyproheptadine or diclofenac on the pharmacokinetics of DMXAA were investigated in male Wistar Kyoto rats. The effects of L-thalidomide, cyproheptadine and diclofenac on microsomal metabolism and plasma protein binding of DMXAA were also investigated.
No significant alteration in the plasma concentration profile for DMXAA was observed following L-thalidomide pretreatment in rats. In contrast, when combined with diclofenac or cyproheptadine, the plasma AUC of DMXAA was significantly (P<0.05) increased by 48% and 88% and the T1/2 by 36% and 107%, respectively, compared to controls. Both diclofenac and cyproheptadine at 500 microM caused a significant inhibition of DMXAA metabolism in rat liver microsomes. In contrast, L-thalidomide had no or little inhibitory effect on DMXAA metabolism in rat liver microsomes except for causing a 32% decrease in 6methylhydroxylation at 500 microM. None of the drugs had a significant effect on the plasma protein binding of DMXAA in the rat.
These studies showed that coadministration of L-thalidomide did not alter the plasma DMXAA AUC in rats, in contrast to previous studies in mice, whereas diclofenac and cyproheptadine significantly reduced the plasma clearance of DMXAA in rats in a similar manner to their effect in mice. The cause of the species difference in the pharmacokinetic response to thalidomide by DMXAA is unknown, and indicates difficulties in predicting the outcome of such a combination in patients.
已表明在小鼠中，沙利度胺、赛庚啶或双氯芬酸与新型抗肿瘤药物5,6 - 二甲基呫吨酮 - 4 - 乙酸（DMXAA）联合给药可增加其血浆浓度 - 时间曲线下面积（AUC）。本研究的目的是在大鼠模型中进一步研究这些DMXAA与药物的药代动力学相互作用。
在雄性Wistar Kyoto大鼠中研究了L - 沙利度胺、赛庚啶或双氯芬酸联合给药对DMXAA药代动力学的影响。还研究了L - 沙利度胺、赛庚啶和双氯芬酸对DMXAA微粒体代谢和血浆蛋白结合的影响。
在大鼠中，L - 沙利度胺预处理后未观察到DMXAA血浆浓度曲线有显著变化。相比之下，与双氯芬酸或赛庚啶联合使用时，与对照组相比，DMXAA的血浆AUC分别显著（P<0.05）增加了48%和88%，T1/2分别增加了36%和107%。500微摩尔的双氯芬酸和赛庚啶均显著抑制大鼠肝微粒体中DMXAA的代谢。相比之下，L - 沙利度胺对大鼠肝微粒体中DMXAA的代谢没有或几乎没有抑制作用，除了在500微摩尔时使6 - 甲基羟基化降低32%。这些药物对大鼠血浆中DMXAA的蛋白结合均无显著影响。
这些研究表明，与之前在小鼠中的研究相反，在大鼠中L - 沙利度胺联合给药不会改变血浆DMXAA的AUC，而双氯芬酸和赛庚啶以与在小鼠中相似的方式显著降低大鼠中DMXAA的血浆清除率。DMXAA对沙利度胺药代动力学反应的种属差异原因尚不清楚，这表明预测患者中这种联合用药的结果存在困难。
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