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首页> 美国卫生研究院文献>British Journal of Cancer >Phase I and pharmacokinetic study of D-verapamil and doxorubicin.
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Phase I and pharmacokinetic study of D-verapamil and doxorubicin.

机译：D-维拉帕米和阿霉素的第一阶段和药代动力学研究。

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The calcium antagonist verapamil (a mixture of D- and L-racemers) is a potent modulator of the multi-drug resistance phenotype in vitro at a concentration of 6 microM. Clinical studies have shown dose-limiting toxicity of hypotension and heart block when plasma levels approach the concentrations active in vitro. Previous data indicate that the D-isomer is less cardioactive than the L-isomer but they appear to be equipotent in reversing drug resistance in vitro. In an attempt to increase plasma verapamil concentrations, we have treated ten patients (total of 27 courses) with oral D-verapamil (DVPM), 150-300 mg 6 h, and doxorubicin i.v. 70 mg m2 q 3 weeks. Hypotension (supine systolic BP less than 100 mmHg or a fall in systolic BP of greater than 30 mmHg) occurred in 5/6 patients at 1200 mg day DVPM, in 1/5 at 800 mg day, and in 1/5 at 600 mg day. PQ prolongation (greater than 0.23 s) was demonstrated in 2/5 patients at 800 mg day DVPM. Plasma levels of DVPM and its active metabolite norverapamil were measured and, combining these, levels of 3-4 microM were achieved at 1200 mg day DVPM; however this dose is likely to lead to unacceptable toxicity in the outpatient setting. Using an oral outpatient schedule of administration, an appropriate dose of DVPM is 800 mg day. This provides a combined plasma level (for VPM and DVPM) of 2-3 microM. If DVPM is to prove useful as a resistance modulator, it may require to be administered intravenously with careful inpatient monitoring and support.
机译：钙拮抗剂维拉帕米（D-和L-外消旋体的混合物）是体外多药耐药表型的有效调节剂，浓度为6 microM。临床研究表明，当血浆水平接近体外活性浓度时，低血压和心脏传导阻滞的剂量限制性毒性。先前的数据表明，D-异构体的心脏活性低于L-异构体，但它们在逆转体外耐药性方面表现出同等效力。为了提高血浆维拉帕米的浓度，我们用口服D-维拉帕米（DVPM），150-300 mg 6 h和阿霉素i.v.治疗了10名患者（总共27个疗程）。 70 mg m2每3周一次。低血压（仰卧收缩压小于100 mmHg或收缩压下降大于30 mmHg）的5/6患者在1200 mg日DVPM，1/5在800 mg日和1/5在600 mg时发生天。在800 mg日DVPM的2/5患者中证实了PQ延长（大于0.23 s）。测量血浆中DVPM及其活性代谢产物诺维拉帕米的水平，并结合起来，在每天1200 mg DVPM时达到3-4 microM的水平；但是该剂量在门诊患者中可能会导致不可接受的毒性。使用口服门诊给药方案，DVPM的适当剂量为800毫克/天。这提供了2-3 microM的组合血浆水平（对于VPM和DVPM）。如果证明DVPM可用作抗性调节剂，则可能需要在住院患者的仔细监测和支持下静脉注射。

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