Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide

Abstract

Introduction: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers.

Methods: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m² (range 37.6-78.6 kg/m²) and weight 151.3 kg (range 112-251.9 kg)] and 20 healthy volunteers [mean weight 70.6 kg (range 58-85 kg)] were included. Morbidly obese patients received 10 mg of intravenous (I.V.) morphine after gastric bypass surgery, with additional morphine I.V. doses as needed. Healthy volunteers received an I.V. bolus of morphine of 0.1 mg/kg followed by an infusion of 0.030 mg kg^-1 h^-1 for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2.

Results: In morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001).

Conclusion: Metabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.

Fig. 1

Schematic of the population pharmacokinetic model of morphine and morphine glucuronides. CL _F formation clearance, CL _E elimination clearance, Ktr transit rate constant, M3G morphine-3-glucuronide, M6G morphine-6-glucuronide, Q inter-compartmental clearance from the central compartment of morphine to the peripheral compartments of morphine, V1 central volume of distribution, V4 _M ,V5 _M peripheral compartments of morphine, V3_M6G = V2_M3G central volumes of morpine glucuronides, CL_{non-glucuronide} = 35% of Cl_total (70 kg), CL_total = Cl_{non-glucuronide} + CL_{F M3G} + CL_{F M6G}

Fig. 2

Goodness-of-fit plots of morbidly obese individuals (n = 20, blue squares) and healthy volunteers (n = 20, red rounds). On the first row morphine (a), second row morphine-3-glucuronide (b), and third row morphine-6-glucuronide (c). Please note the scale differences in the y-axis. conc. concentration, NPDE normalized prediction distribution error

Fig. 3

Post-hoc parameters estimates of morbidly obese individuals (n = 20, blue squares) and healthy volunteers (n = 20, red rounds) from the final model vs. total body weight, including morphine-3-glucuronide elimination clearance (CL_E M3G) vs. total body weight (a), morphine-6-glucuronide elimination clearance (CL_E M6G) vs. total body weight (b), morphine-3-glucuronide transit rate constant (Ktr) vs. total body weight (c), morphine-6-glucuronide transit rate constant (Ktr2) vs. total body weight (d), peripheral volume of distribution of morphine (V1_M) vs. total body weight (e), and formation clearance of morphine-6-glucuronide (CL_F M6G) vs. total body weight (f)

Fig. 4

Population predicted morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) concentrations over time in four typical study patients (56, 75, 125, and 253 kg) after a 10-mg intravenous bolus dose of morphine hydrochloride (a–c) and a 2-mg/h continuous infusion of morphine hydrochloride for 48 h (d–f)