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

The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the <i>ABCB1</i> 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 <i>ABCB1</i> 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, <i>p</i> < 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, <i>p</i> = 0.03). Adiponectin was inversely correlated with morphine <i>C</i>_max (rs = −0.44, <i>p</i> = 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 <i>ABCB1</i> 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