Pero R W, Olsson A, Simanaitis M, Amiri A, Andersen I
Department of Cell and Molecular Biology, University of Lund, Sweden.
Pharmacol Toxicol. 1997 May;80(5):231-9. doi: 10.1111/j.1600-0773.1997.tb01965.x.
Metoclopramide is a drug which has experienced worldwide use in the clinic for over 30 years as an antiemetic. Recently, it has also been shown to possess radio- and chemosensitizing properties in both animal tumour models and humans at the higher dose of 2 mg/kg. Two new metoclopramide formulations are being clinically developed and they differ mainly in whether the pH of their formulations are acidic (pH 2.5-3.5) or neutral (pH 6.5-7.0). Here we report that intramuscular administration of neutral metoclopramide is about 100% bioavailable, safer and with reduced side effects compared to acidic metoclopramide delivered by intramuscular injection to rats within the dose range of 3.5 to 14 mg/kg. The intramuscular administration of metoclopramide was also about 100% bioavailable compared to the intravenous route of administration. Furthermore, neutral metoclopramide had significantly decreased affinity for dopamine D2 receptors and increased affinity for 5-hydroxytryptamine, receptors, but the radiosensitizing potency was the same, when compared to equimolar concentrations of acidic metoclopramide. Taken together these data support the continued development of neutral metoclopramide for high dose intramuscular administration of metoclopramide for future clinical use as both an antiemetic and radiosensitizer.
甲氧氯普胺是一种作为止吐药已在临床上全球使用超过30年的药物。最近，在动物肿瘤模型和人体中也已显示，在2mg/kg的较高剂量下它具有放射增敏和化学增敏特性。两种新的甲氧氯普胺制剂正在进行临床开发，它们的主要区别在于制剂的pH是酸性（pH 2.5 - 3.5）还是中性（pH 6.5 - 7.0）。在此我们报告，在3.5至14mg/kg的剂量范围内，与给大鼠肌肉注射酸性甲氧氯普胺相比，肌肉注射中性甲氧氯普胺的生物利用度约为100%，更安全且副作用减少。与静脉给药途径相比，肌肉注射甲氧氯普胺的生物利用度也约为100%。此外，与等摩尔浓度的酸性甲氧氯普胺相比，中性甲氧氯普胺对多巴胺D2受体的亲和力显著降低，对5 - 羟色胺受体的亲和力增加，但放射增敏效力相同。综合这些数据支持继续开发中性甲氧氯普胺用于高剂量肌肉注射甲氧氯普胺，以便未来作为止吐药和放射增敏剂用于临床。
