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

Sjoerd de Hoogd, Pyry A J Välitalo, Albert Dahan, Simone van Kralingen, Michael M W Coughtrie, Eric P A van Dongen, Bert van Ramshorst, Catherijne A J Knibbe, Sjoerd de Hoogd, Pyry A J Välitalo, Albert Dahan, Simone van Kralingen, Michael M W Coughtrie, Eric P A van Dongen, Bert van Ramshorst, Catherijne A J Knibbe

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.

Conflict of interest statement

Funding

No sources of funding were used in the preparation of this article.

Conflict of Interest

Sjoerd de Hoogd, Pyry A. J. Välitalo, Albert Dahan, Simone van Kralingen, Michael M. W. Coughtrie, Eric P. A. van Dongen, Bert van Ramshorst, and Catherijne A. J. Knibbe have no conflicts of interest directly relevant to the content of this article.

Ethics Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Schematic of the population pharmacokinetic model of morphine and morphine glucuronides. CLF formation clearance, CLE 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, V4M,V5M peripheral compartments of morphine, V3M6G = V2M3G central volumes of morpine glucuronides, CLnon-glucuronide = 35% of Cltotal (70 kg), CLtotal = Clnon-glucuronide + CLF M3G + CLF M6G
Fig. 2
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
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 (CLE M3G) vs. total body weight (a), morphine-6-glucuronide elimination clearance (CLE 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 (V1M) vs. total body weight (e), and formation clearance of morphine-6-glucuronide (CLF M6G) vs. total body weight (f)
Fig. 4
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)

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