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Self-micellization of gemfibrozil 1-O-beta acyl glucuronide in aqueous solution
David M Shackleford1, Richard J Prankerd, Martin J Scanlon
1Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
Purpose:
Phase II metabolism involves the conjugation of a polar moiety, such as sulfate or glucuronic acid, to a (relatively) nonpolar xenobiotic. Although it might be expected that such conjugates may exhibit amphiphilic character (e.g., surface activity and potential to form micelles), no detailed study of the micellization characteristics of any drug-glucuronide conjugates has yet been reported. Therefore, the aim of this study was to investigate the solution behavior and amphiphilic characteristics of gemfibrozil 1-O-beta glucuronide (GG), a model drug-glucuronide conjugate.
Methods:
Crude GG was extracted from the urine of volunteers dosed with 600 mg of gemfibrozil, and this material was then purified by reversed-phase high-performance liquid chromatography to yield a white solid. The amphiphilic properties of GG within the bulk aqueous phase were studied by isothermal titration microcalorimetry and 1H-NMR spectrometry, whereas those at the aqueous/air interface were studied by surface tensiometry.
Results:
The results of each independent analytical technique were consistent with GG in aqueous solution exhibiting amphiphilic properties typical of a hydrophilic surfactant. The titration microcalorimetry and 1H-NMR spectrometry data were in excellent agreement with each other, yielding critical micellization concentrations (cmc) for GG in 0.1 M acetate buffer of 18.1 +/- 0.4 mM and 18.3 +/- 0.3 mM, respectively. The profile and results of the surface tension measurements were consistent with GG localizing at the aqueous/air interface.
Conclusions:
These results confirm the hypothesis that a glucuronide conjugate of a relatively nonpolar xenobiotic, such as gemfibrozil, behaves as an amphiphile in aqueous solution. The implications of this observation include a likely basis for the previously observed concentration-dependence in the degradation rate of the acyl glucuronides of 2-phenylpropionic acid, as well as identifying a possible broader contributory effect to the structural dependencies in biliary choleresis of different glucuronide conjugates of xenobiotics.