Glyceride derivatives as potential prodrugs: synthesis, biological activity and kinetic studies of glyceride derivatives of mefenamic acid.
In order to reduce the gastrointestinal side effect, of mefenamic acid, its carboxylic group was condensed with the hydroxyl group of 1,2,3-trihydroxy propane 1,3-dipalmitate/stearate to give 3a and 3b. These compounds were evaluated for their gastric toxicity, anti-inflammatory activity by the carageenan induced paw oedema test and analgesic activity by the acetic acid induced writhing method. The release of mefenamic acid from the esters 3a and 3b was studied at pH 3, 4, 5 and 7.4 with direct analysis by reverse phase HPLC using acetonitrile:acetate buffer (0.1 M, pH 3.5): methanol (40:25:35) at 1 mL/min. The prodrugs showed less hydrolysis at pH 5 compared to pH 7.4 indicating that the prodrugs do not dissociate at stomach pH but release mefenamic acid at pH 7.4 in adequate amounts. The hydrolysis studies were also performed in rat plasma. A higher plasma concentration of mefenamic acid was observed in animals treated with 3a and 3b compared to the animals treated with the parent drug, and even after 8 h the concentration of mefenamic acid was 2 times higher. The peak plasma concentration of mefenamic acid in animals treated with mefenamic acid was attained in 1.5 h compared with 2 h in the case of prodrugs treated animals. The prodrugs showed less gastric ulceration compared to mefenamic acid at 100 mg/kg, a severity index of 1.10, 1.22 being observed with 3a, 3b and with mefenamic acid a severity index of 2.37 was observed. The prodrugs showed better anti-inflammatory activity compared to the parent drug and analgesic activity comparable to the parent drug. These findings suggest that the prodrugs 3a and 3b synthesized might be used as biolabile prodrugs of mefenamic acid with increased bioavailability and less gastrointestinal side effects.
Khan
M S Y
MS
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi, India. msykhan@hotmail.com
Akhter
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002351:Carrageenan; D002851:Chromatography, High Pressure Liquid; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005989:Glycerides / Q000493:pharmacokinetics / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007202:Indicators and Reagents; D008297:Male; D008528:Mefenamic Acid / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D013696:Temperature
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005989:Glycerides; D007202:Indicators and Reagents; D011355:Prodrugs; D008528:Mefenamic Acid; D002351:Carrageenan