Gastrointestinal safety and therapeutic efficacy of parenterally administered phosphatidylcholine-associated indomethacin in rodent model systems.
OBJECTIVE
Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that is limited in its enteral or parenteral use by side effects of gastroduodenal bleeding and ulceration. We have investigated the ability of phosphatidylcholine associated with indomethacin to form a therapeutically effective drug (INDO-PC) with reduced gastrointestinal (GI) toxicity for parenteral use.


METHODS
Rats were treated acutely by intravenous or chronically with subcutaneous injection of vehicle, indomethacin or INDO-PC using three related protocols. We then evaluated the following properties of these parenterally administered test drugs: (i) GI toxicity (luminal and faecal haemoglobin; intestinal perforations and adhesions; and haematocrit); (ii) bioavailability (plasma indomethacin); and (iii) therapeutic efficacy (analgesia from sensitivity to pressure; anti-inflammatory from ankle thickness; cyclo-oxygenase (COX) inhibition from synovial fluid prostaglandin E(2) concentration) in rats with adjuvant-induced joint inflammation.


RESULTS
Acute and chronic dosing with INDO-PC produced less GI bleeding and intestinal injury than indomethacin alone, whereas the bioavailability, analgesic, anti-inflammatory and COX inhibitory activity of INDO-PC were comparable to indomethacin.


CONCLUSIONS
The chemical association of phosphatidylcholine with indomethacin appears to markedly reduce the GI toxicity of the NSAID while providing equivalent therapeutic efficacy in a parenteral INDO-PC formulation.
The University of Texas Health Science Center at Houston, Medical School, Houston, Texas 77030, USA.
L  M
L
Lichtenberger
J J
JJ
Romero
E J
EJ
Dial
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D015232:Dinoprostone / Q000032:analysis; D004333:Drug Administration Routes; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced*; D007213:Indomethacin / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D023421:Models, Animal; D010713:Phosphatidylcholines / Q000737:chemistry*; D011863:Radioimmunoassay; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010713:Phosphatidylcholines; D015232:Dinoprostone; D007213:Indomethacin