Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers

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• 作者：Célia Lloret-Linares ; Eisuke Miyauchi ; Huilong Luo ; Laurence Labat ; Jean-Luc Bouillot ; Christine Poitou ; Jean-Michel Oppert ; Jean-Louis Laplanche ; Stéphane Mouly ; Jean-Michel Scherrmann ; Yasuo Uchida ; Masanori Tachikawa ; Tetsuya Terasaki ; Jean-François Bergmann ; Xavier Declèves
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：March 7, 2016
• 年：2016
• 卷：13
• 期：3
• 页码：766-773
• 全文大小：317K
• ISSN：1543-8392

文摘

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/m². The metabolic ratios AUC_0-inf M3G/morphine and AUC_0-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 AUC_0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine C_max (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.