Kashihara Yushi, Terao Yui, Yoda Kensaku, Hirota Takeshi, Kubota Toshio, Kimura Miyuki, Matsuki Shunji, Hirakawa Masaaki, Irie Shin, Ieiri Ichiro
Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Hospital Pharmacy, Fukuoka Tokushukai Medical Center, Fukuoka, Japan.
Eur J Clin Pharmacol. 2019 Mar;75(3):351-361. doi: 10.1007/s00228-018-2568-4. Epub 2018 Oct 31.
Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA).
The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa.
In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa.
This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.
氧化镁（MgO）常与左旋多巴/卡比多巴（LDCD）联合使用，以改善帕金森病患者的便秘症状。已有研究表明，左旋多巴与氧化镁混合会导致左旋多巴降解；然而，尚未有针对人类的相互作用研究。我们提出了LDCD与MgO相互作用的机制，并在大鼠和人类身上进行了药代动力学研究。为了评估MgO治疗的药效学变化，我们应用了基于模型的荟萃分析（MBMA）。
在体外研究中评估了MgO对左旋多巴和卡比多巴稳定性的影响。我们在大鼠和健康志愿者身上进行了MgO与LDCD的药代动力学相互作用研究。进行了一项开放标签、非随机、单臂、两阶段的临床研究。在MBMA中，我们构建了左旋多巴的群体药代动力学/药效学模型，并预测了MgO治疗对左旋多巴药效学的影响。
体外结果表明，卡比多巴在碱性pH条件下不稳定。在大鼠口服MgO/口服LDCD后，血浆LDCD浓度降低，但口服MgO/静脉注射LDCD治疗后未出现这种情况，这表明胃肠道是相互作用的部位。一项健康志愿者研究表明，MgO还分别使左旋多巴和卡比多巴的AUC显著降低了35.3%和80.9%。基于模型的模拟表明，MgO治疗对左旋多巴的有效性不利。
这是第一项表明LDCD与MgO在人类中存在明确药代动力学相互作用的研究。需要进一步研究以确认MgO对左旋多巴药效学的影响。
