Vol. 298, Issue 1, 279-287, July 2001

Phosphatidylcholine Association Increases the Anti-Inflammatory and Analgesic Activity of Ibuprofen in Acute and Chronic Rodent Models of Joint Inflammation: Relationship to Alterations in Bioavailability and Cyclooxygenase-Inhibitory Potency

Lenard M. Lichtenberger, Jimmy J. Romero, Winanda M. J. de Ruijter, Fariba Behbod, Rebecca Darling, Anis Q. Ashraf and Sudershan K. Sanduja

Department of Integrative Biology and Pharmacology, The University of Texas Medical School, Houston, Texas (L.M.L., J.J.R., W.M.J.deR., F.B., R.D.); and Natural Therapeutics, Sugar Land, Texas (A.Q.A., S.K.S.)

We investigated whether chemical association of phosphatidylcholine (PC) to ibuprofen enhances the anti-inflammatory/analgesic activity of the nonsteroidal anti-inflammatory drug (NSAID) and whether any change in therapeutic action is due to alterations in drug bioavailability and cyclooxygenase (COX) inhibitory activity. Acute/chronic joint inflammation was induced in rats, by injection of Complete Freund's Adjuvant. In the acute study, rats were administered saline, ibuprofen, or PC-ibuprofen (at NSAID doses of 10, 25, and 50 mg/kg), and 2 h later the pain threshold of the affected joint to pressure was measured. PC-ibuprofen increased the pain threshold at all NSAID doses, whereas unmodified ibuprofen demonstrated analgesic activity at only the highest dose. In the chronic study, we investigated the effects of saline, PC-ibuprofen, and ibuprofen (administered at 15 and 25 mg/kg/day) on ankle thickness and pain threshold, and demonstrated that PC-ibuprofen had significantly greater anti-inflammatory and analgesic activity than ibuprofen, over a 30- to 60-day period. PC association resulted in reduced uptake (decreased C_max), a modest increase in the area under the curve, and a longer t_1/2 of ibuprofen. We also demonstrated that PC-ibuprofen was a comparable or a more effective inhibitor of both 6-keto-prostaglandin F₁ concentration of fluid collected from tissue in and around the inflamed stifle joint, and COX-2 activity in activated human umbilical vein endothelial cells. In conclusion, we have demonstrated that PC association results in increases in ibuprofen's anti-inflammatory and analgesic activity in rodent models of acute and chronic joint inflammation, and this effect may relate to alterations in drug bioavailability and COX-inhibitory potency.