title: Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers.
abstract: 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.
authors.affiliation: 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.
authors.forename: Célia
authors.initials: C
authors.lastname: Lloret-Linares
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Miyauchi
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris F-75010, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Pharmacokinetics and Pharmacochemistry Unit, Paris F-75014, France.
authors.forename: Huilong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris F-75010, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Pharmacokinetics and Pharmacochemistry Unit, Paris F-75014, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Labat
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Université Versailles Saint Quentin, Department of Surgery, Boulogne 92100, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bouillot
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service de Nutrition, Université Pierre et Marie Curie, Institut cardiométabolisme et nutrition (ICAN), Paris F-75013, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Poitou
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service de Nutrition, Université Pierre et Marie Curie, Institut cardiométabolisme et nutrition (ICAN), Paris F-75013, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Oppert
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris F-75010, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Laplanche
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouly
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris F-75010, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.affiliation: Membrane Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai 980-8578, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.affiliation: 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.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bergmann
authors.affiliation: Inserm, UMR-S 1144 Université Paris Descartes-Paris Diderot, Variabilité de réponse aux psychotropes, Paris F-75010, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Pharmacokinetics and Pharmacochemistry Unit, Paris F-75014, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000032:analysis*; D015992:Body Mass Index; D051544:Cytochrome P-450 CYP3A; D005260:Female; D020719:Glucuronides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009767:Obesity, Morbid / Q000188:drug therapy / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D015415:Biomarkers; D051544:Cytochrome P-450 CYP3A; D020719:Glucuronides; D014453:Glucuronosyltransferase; D009020:Morphine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C114462:multidrug resistance-associated protein 3; C491474:UGT2B7 protein, human
keywords: MDR1; glucuronidation; morphine; obesity; pharmacokinetics; small intestine; transporters