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

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

研究成果: Article

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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 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.

元の言語English
ページ(範囲)766-773
ページ数8
ジャーナルMolecular Pharmaceutics
13
発行部数3
DOI
出版物ステータスPublished - 2016 3 7

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

フィンガープリント Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

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    Lloret-Linares, C., Miyauchi, E., Luo, H., Labat, L., Bouillot, J. L., Poitou, C., Oppert, J. M., Laplanche, J. L., Mouly, S., Scherrmann, J. M., Uchida, Y., Tachikawa, M., Terasaki, T., Bergmann, J. F., & Declèves, X. (2016). Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers. Molecular Pharmaceutics, 13(3), 766-773. https://doi.org/10.1021/acs.molpharmaceut.5b00656