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Hoogd, S. de; Välitalo, P.A.J.; Dahan, .A.; Kralingen, S. van; Coughtrie, M.M.W.; Dongen, E.P.A. van; ... ; Knibbe, C.A.J. (2017)

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

Article / Letter to editor
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.\n for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2.\nIn 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).\nMetabolism 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...Show moreObesity 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.\n for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2.\nIn 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).\nMetabolism 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.\nINTRODUCTION\nMETHODS\nRESULTS\nCONCLUSIONShow less
All authors
Hoogd, S. de; Välitalo, P.A.J.; Dahan, .A.; Kralingen, S. van; Coughtrie, M.M.W.; Dongen, E.P.A. van; Ramshorst, B. van; Knibbe, C.A.J.
Date
2017-05-16
Journal
Clinical Pharmacokinetics
Volume
56
Issue
12
Pages
1577 - 1587
DOI
doi:10.1007/s40262-017-0544-2