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Pharmaceuticals 2012, 5(10), 1080-1091; doi:10.3390/ph5101080
Article

Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers

1,*  and 2
Received: 3 September 2012; in revised form: 30 September 2012 / Accepted: 8 October 2012 / Published: 12 October 2012
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Abstract: The free –COOH present in NSAIDs is thought to be responsible for the GI irritation associated with all traditional NSAIDs. Exploitation of mutual prodrugs is an approach wherein the NSAID is covalently bounded to a second pharmacologically active carrier/drug with the ultimate aim of reducing the gastric irritation. In this study some NSAIDs were conjugated with gabapentin via ester bonds using glycol spacers with the expectation of reducing gastric adverse effects and obtaining synergistic analgesic effects. The kinetics of ester hydrolysis were studied in two different non enzymatic buffer solutions at pH 1.2 and 7.4, as well as in 80% human plasma using HPLC with chloroform -methanol as mobile phase. Compounds 9ac with ethylene glycol spacers showed significant stability at buffer solutions with half lives ranging from about 8–25 h, while the underwent a reasonable plasma hydrolysis (49%–88%) in 2 h. Compound 9d with a propylene glycol spacer shows a higher rate of enzymatic hydrolysis than the corresponding ethylene glycol compound 9c. The result of compounds 9a-c indicate that these compounds may be stable during their passage through the GIT until reaching the blood circulation.
Keywords: NSAIDs; gastric irritation; mutual prodrug; gabapentin; HPLC NSAIDs; gastric irritation; mutual prodrug; gabapentin; HPLC
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Mahdi, M.F.; Alsaad, H.N. Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers. Pharmaceuticals 2012, 5, 1080-1091.

AMA Style

Mahdi MF, Alsaad HN. Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers. Pharmaceuticals. 2012; 5(10):1080-1091.

Chicago/Turabian Style

Mahdi, Monther F.; Alsaad, Hiba N. 2012. "Design, Synthesis and Hydrolytic Behavior of Mutual Prodrugs of NSAIDs with Gabapentin Using Glycol Spacers." Pharmaceuticals 5, no. 10: 1080-1091.


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