Ung D, Parkman H P, Nagar S
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
Xenobiotica. 2009 Oct;39(10):749-56. doi: 10.1080/00498250903096121.
This study examined in vitro interaction between domperidone and erythromycin. Both are prescribed for refractory gastroparesis. Domperidone is metabolized via human cytochrome P4503A4. Erythromycin is a CYP3A4 inhibitor. Incubations evaluated domperidone metabolite formation in human liver microsomes and recombinant CYP3A4. Concentration- and time-dependent inhibition of 500 microM domperidone was studied with 2.5-200 microM erythromycin over 10-40 min. Domperidone metabolite (5-hydroxy domperidone, M3) formation was inhibited by erythromycin in a concentration- and time-dependent manner. The K(I) estimate was 18.4 microM in human liver microsomes and 4.1 microM in CYP3A4. Using a model incorporating CYP3A4 hepatic and gut inhibition, in vitro estimates from human liver microsomes and CYP3A4 were used to predict in vivo AUCi/AUC ratios of 2.54 and 4.95, respectively. Significant inhibition of domperidone metabolism by erythromycin occurs. This predicts greater domperidone drug exposure when used with erythromycin. This important drug-drug interaction will be evaluated in future human studies.
本研究检测了多潘立酮与红霉素的体外相互作用。二者均被用于治疗难治性胃轻瘫。多潘立酮通过人细胞色素P4503A4进行代谢。红霉素是一种CYP3A4抑制剂。通过在人肝微粒体和重组CYP3A4中孵育来评估多潘立酮代谢物的形成。在10 - 40分钟内，用2.5 - 200微摩尔的红霉素研究了500微摩尔多潘立酮的浓度和时间依赖性抑制作用。红霉素以浓度和时间依赖性方式抑制多潘立酮代谢物（5 - 羟基多潘立酮，M3）的形成。在人肝微粒体中的K（I）估计值为18.4微摩尔，在CYP3A4中为4.1微摩尔。使用包含CYP3A4肝脏和肠道抑制作用的模型，来自人肝微粒体和CYP3A4的体外估计值分别用于预测体内AUCi/AUC比值为2.54和4.95。红霉素对多潘立酮代谢有显著抑制作用。这预示着与红霉素合用时多潘立酮的药物暴露量会增加。这种重要的药物相互作用将在未来的人体研究中进行评估。
