Stereoselective binding properties of naproxen glucuronide diastereomers to proteins |
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Authors: | Alfred Bischer Parnian Zia-Amirhosseini Masahiro Iwaki Antony F. McDonagh Leslie Z. Benet |
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Affiliation: | (1) Department of Pharmacy, University of California, 513 Parnassus Avenue, 94143-0446 San Francisco, California;(2) Department of Medicine and the Liver Center, University of California, 513 Parnassus Avenue, 94143-0538 San Francisco, California;(3) Present address: Hoechst AG, Brüningstrasse 50, PQH 790, 65929 Frankfurt am Main, Germany;(4) Present address: Faculty of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, 577 Higashi-Osaka, Japan |
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Abstract: | The stability of naproxen glucuronide (NAP-G) diastereomers was investigated in buffer, 0.3% and 3% human serum albumin (HSA) solutions, and human plasma.R-NAP-G was found to be less stable in phosphate buffer than itsS-diastereomer, whereas incubation media containing protein in general increased the degradation rate of NAP-G but also caused a change of the stereoselective stability where theR-NAP-G was more stable thanS-NAP-G. Reversible binding of NAP-Gs to HSA (0.3%) was investigated and compared with the corresponding properties of naproxen (NAP) enantiomers. NAP-G diastereomers exibited a considerable and stereoselective affinity to HSA, although less than that observed for the NAP enantiomers.In vitro irreversible binding of NAP-Gs to HSA, human and rat plasma proteins was also investigated. Irreversible binding was higher forR-NAP-G (50 μM) than forS-NAP-G (50 μM) in all incubation media. This stereoselective difference was observed with HSA containing medium as well as in rat and human plasma. Incubation with unconjugated NAP did not lead to irreversible binding. Preincubation of HSA with acetylsalicylic acid (≈ 11 mM) and glucuronic acid (50 mM) decreased the extent of irreversible binding suggesting involvement of lysine residues for covalent binding. Preincubation withS-NAP also decreased the irreversible binding yield. This paper is dedicated to Professor Richard Neidlein, Pharmaceutical Chemistry Institute, Heidelberg, in commemoration of his 65th birthday. Supported in part by National Institutes of Health Grants GM 36633 and DK 26307. |
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Keywords: | naproxen naproxen glucuronide stereoselective binding covalent binding reversible binding degradation rates acyl glucuronides |
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