CYP450 活性在 Roux-en-Y 胃旁路前后的变化：与肠道和肝脏含量的相关性。
CYP450 activities before and after Roux-en-Y gastric bypass: correlation with their intestinal and liver content.
机构信息
Célia Lloret-Linares, Maladies Nutritionnelles et métaboliques, Ramsay-Générale de Santé, Hôpital Privé Pays de Savoie, Annemasse, France; Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Therapeutic Research Unit, Department of Internal Medicine, Paris, France.
Geneva University Hospitals & Faculty of Medicine, University of Geneva, Geneva, Switzerland.
出版信息
Surg Obes Relat Dis. 2019 Aug;15(8):1299-1310. doi: 10.1016/j.soard.2019.05.019. Epub 2019 May 20.
BACKGROUND
Several anatomic and physiologic changes occur after Roux-en-Y gastric bypass (RYGB) and its associated weight loss. At present, no single unified model can predict changes in drug metabolism associated with either RYGB surgery or weight loss.
OBJECTIVE
The aim of this longitudinal human study was to measure the activity of the 5 most important Cytochrome P450 (CYP) involved in drug metabolism in patients with obesity before and after RYGB. Jejunal and liver biopsies obtained during bariatric surgery were used to measure CYP amount, and correlation between jejunal and hepatic content was estimated.
SETTING
French university hospital.
METHODS
Eleven volunteers with a mean body mass index of 44.1 (39.4-50.0) kg/m participated in the study. CYP1 A2, CYP2 C9, CYP2 C19, CYP2 D6, and CYP3 A4/A5 activities were measured with a cocktail approach before surgery (visit 1), 5 to 8 weeks after surgery (visit 2), and 25 to 30 weeks after surgery (visit 3).
RESULTS
CYP3 A4/A5 and CYP2 C9 metabolic ratios were transitorily and significantly increased immediately after surgery (visit 2 versus 1). RYGB procedure does not lead to significant change in CYP activity 25 to 30 weeks after surgery (visit 3 versus 1). Samples obtained during surgery showed significant correlation between intestinal and liver contents of CYP2 C9 and CYP3 A4/A5. Except for liver CYP1 A2 content, CYP metabolic activities were not correlated to their intestinal or liver contents.
CONCLUSIONS
This study showed that RYGB does not lead to a significant change in CYP activity 25 to 30 weeks after surgery. However, CYP3 A4/A5 and CYP2 C9 activities were transitorily and significantly increased in the immediate postoperative context (<1 mo), representing a situation at risk of reduced drug exposure for several drugs that have a narrow therapeutic window. In addition, considering high interindividual variability in liver contents and activity of CYP3 A4 and CYP2 C9, patients receiving drugs highly metabolized by these 2 CYPs should be closely monitored in the immediate postoperative period.
背景
Roux-en-Y 胃旁路术（RYGB）及其相关减重术后会发生多种解剖和生理变化。目前，尚无单一的统一模型可以预测 RYGB 手术或体重减轻相关的药物代谢变化。
目的
本纵向人体研究旨在测量肥胖患者 RYGB 术前和术后 5 种最重要的与药物代谢相关的细胞色素 P450（CYP）的活性。在减肥手术期间获得的空肠和肝活检用于测量 CYP 量，并估计空肠和肝内容物之间的相关性。
地点
法国大学医院。
方法
11 名平均体重指数为 44.1（39.4-50.0）kg/m2 的志愿者参与了这项研究。在手术前（第 1 次就诊）、手术后 5-8 周（第 2 次就诊）和手术后 25-30 周（第 3 次就诊）时，使用鸡尾酒方法测量 CYP1A2、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4/5 活性。
结果
CYP3A4/5 和 CYP2C9 代谢比在手术后立即短暂且显著增加（第 2 次就诊与第 1 次就诊相比）。RYGB 手术后 25-30 周（第 3 次就诊与第 1 次就诊相比）不会导致 CYP 活性显著变化。手术期间获得的样本显示，CYP2C9 和 CYP3A4/5 的肠道和肝脏含量之间存在显著相关性。除了肝 CYP1A2 含量外，CYP 代谢活性与肠道或肝脏含量均无相关性。
结论
本研究表明，RYGB 术后 25-30 周 CYP 活性无明显变化。然而，CYP3A4/5 和 CYP2C9 活性在术后即刻（<1 个月）短暂且显著增加，这代表了几种治疗窗较窄的药物暴露减少的风险情况。此外，考虑到 CYP3A4 和 CYP2C9 的肝含量和活性存在较高的个体间变异性，应在术后即刻密切监测接受这些 2 种 CYP 高度代谢药物的患者。
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