Paracetamol (acetaminophen) esters of some non-steroidal anti-inflammatory carboxylic acids as mutual prodrugs with improved therapeutic index.
Paracetamol (acetaminophen) esters [4a-f] of some acidic NSAIDs were synthesized and evaluated as mutual prodrug forms with the aim of improving the therapeutic index through prevention of the gastrointestinal toxicity. The structures of the synthesized esters were confirmed by IR and (1)H-NMR spectroscopy and their purity was established by elemental analyses and TLC. In-vitro stability studies revealed that the synthesized ester prodrugs 4a-f are sufficiently chemically stable in non-enzymatic simulated gastric fluid (hydrochloric acid buffer of pH 1.3 (t (1/2) approximately 15-45 h)) and in phosphate buffer of pH 7.4 (t (1/2) approximately 4-40 h). In 80% human plasma and 10% rat liver homogenate, the mutual prodrugs were found to be susceptible to enzymatic hydrolysis releasing the corresponding NSAID and paracetamol at relatively faster rates (t (1/2) approximately 15-385 min and 1-140 min, respectively). Calculated log P values indicated that the prodrugs 4a-f are more lipophilic than the parent drugs.In-vivo experiments in rabbits showed higher plasma levels of ibuprofen after oral administration of its ester prodrug 4b compared with those resulting from an equivalent amount of the corresponding physical mixture. Moreover, significant improvement in latency of pain threshold in mice has been observed up to 4 h after po administration of 0.02 mmol/kg of the prodrugs, compared with the corresponding physical mixtures. Gross observations and scanning electromicrographs of the stomach showed that the prodrugs induced very little irritancy in the gastric mucosa of mice after oral administration for 4 days. These results suggest that the synthesized mutual ester prodrugs were characterized by a better therapeutic index than the parent drugs.
Fadl
T A
TA
Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, 71526, Assiut, Egypt.
Omar
F A
FA
J Pharm Pharmacol. 1980 Nov;32(11):795-6
6110734
Eur J Med Chem. 1996;31(10):819-25
22026938
J Med Chem. 1995 Sep 29;38(20):3983-94
7562932
Arch Pharm (Weinheim). 1996 Aug-Sep;329(8-9):417-20
8915104
Arch Pharm (Weinheim). 1996 Dec;329(12):554-5
9038424
J Pharm Sci. 1992 Feb;81(2):149-54
1545354
Toxicol Appl Pharmacol. 1979 Sep 15;50(2):283-9
505458
Pharmacol Biochem Behav. 1983 Aug;19(2):251-6
6314388
J Pharm Sci. 1981 Aug;70(8):881-5
7310656
Toxicol Pathol. 1988;16(2):251-9
3142030
J Pharm Pharmacol. 1996 May;48(5):479-85
8799871
Biol Pharm Bull. 1996 Sep;19(9):1178-83
8889037
Arch Toxicol. 1990;64(3):210-7
2115324
JAMA. 1971 Oct 18;218(3):440-1
5109868