Lloret-Linares Célia, Miyauchi Eisuke, Luo Huilong, Labat Laurence, Bouillot Jean-Luc, Poitou Christine, Oppert Jean-Michel, Laplanche Jean-Louis, Mouly Stéphane, Scherrmann Jean-Michel, Uchida Yasuo, Tachikawa Masanori, Terasaki Tetsuya, Bergmann Jean-François, Declèves Xavier
Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris F-75010, France.
Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Therapeutic Research Unit, Department of Internal Medicine, Paris F-75010, France.
Mol Pharm. 2016 Mar 7;13(3):766-73. doi: 10.1021/acs.molpharmaceut.5b00656. Epub 2016 Jan 22.
The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.
我们研究的目的是在病态肥胖受试者群体中，研究空肠中P-糖蛋白（P-gp）、多药耐药相关蛋白2（MRP2）、多药耐药相关蛋白3（MRP3）、尿苷二磷酸葡萄糖醛酸基转移酶2B7（UGT2B7）、细胞色素P450 3A4（CYP3A4）的表达水平、ABCB1基因c.3435C>T多态性与几种肥胖相关生物标志物之间的关联，以及口服吗啡及其葡萄糖醛酸苷的药代动力学。对拟行减肥手术的肥胖患者进行了口服吗啡（30mg）及其葡萄糖醛酸苷的药代动力学研究。手术过程中保留了一段空肠黏膜。对受试者进行ABCB1单核苷酸多态性（SNP）c.3435C>T基因分型。受试者为6名男性和23名女性，平均体重指数为44.8（35.4 - 61.9）kg/m²。代谢比AUC0-inf M3G/吗啡和AUC0-inf M6G/吗啡高度相关（rs = 0.8，p < 0.0001），分别为73.2±24.6（34.7 - 137.7）和10.9±4.1（3.8 - 20.6）。吗啡及其葡萄糖醛酸苷的药代动力学参数与空肠中P-gp、CYP3A4、MRP2和MRP3的含量无关。UGT2B7的空肠含量与吗啡AUC0-inf呈正相关（rs = 0.4，p = 0.03）。脂联素与吗啡Cmax呈负相关（rs = -0.44，p = 0.03）。所研究的因素均与吗啡代谢比无关。药物转运体和代谢酶的空肠含量、ABCB1基因多态性以及低度炎症的个体间差异并不能解释吗啡及其葡萄糖醛酸苷暴露的差异。高吗啡代谢比表明病态肥胖患者吗啡葡萄糖醛酸化增加。
