The effect of morbid obesity on morphine glucuronidation

The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30 mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n =25; mean BMI =43.2 (35.4-61.9) kg/m(2)), 7-15 days (n =16) and 6 months after RYGB (n=19; mean BMI =32.3 (25.4-46.0) kg/m(2)). Morphine C-max and AUC(0-inf) were significantly increased and morphine T-max significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio(0-inf) M3G+ M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p = 0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho =0.5, p <= 0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC(0-inf) should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine. (C) 2016 Elsevier Ltd. All rights reserved.