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Canadian Pharmacy |
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Preclinical Studies
Animal Toxicology
Mesalamine, the active ingredient in Asacol tablets, it has been thoroughly
tested that Asacol is safe for animal studies using both high bioavailability
dose forms and a low bioavailability form. Mesalamine is structurally related
to phenacetin and the salicylates, both are the causes of renal damages
in animals and may be nephrotoxic in humans after prolonged use. Taking
high doses of mesalamine resulted in renal and gastrointestinal lesions
in animals.
Intravenous and Uncoated Oral Mesalamine Studies
Large intravenous doses ranging from 214 to 872 mg/kg/d in rats resulted
at necrosis of the renal medulla and cortex. Renal damage also occurs in
monkeys if they are taking single oral dose of 500 mg/kg. Short-term administration
of high doses of uncoated oral mesalamine (360 mg/kg/d to 1080 mg/kg/d)
was concerned with gastrointestinal bleeding and ulceration in the rat model.
As per long-term animal studies, the kidney was the major target organ for
toxicity. Uncoated mesalamine administered to rats at doses of 170 mg/kg/d
for 6 months caused mild histologic renal damage, and at higher doses (320-360
mg/kg/d) caused renal papillary necrosis. In the studies of dogs, renal
damage or papillary necrosis occurred following dosing with uncoated mesalamine
at 60-80 mg/kg/d for 1 year.
Coated Mesalamine (Asacol Tablets) Study
Previous studies of toxicology were performed with uncoated mesalamine dosage
forms which provided very high systemic availability of mesalamine at dosages
far exceeding normal therapeutic doses in humans. A chronic study in dogs
using an Eudragit-S-coated, low bioavailability oral dosage form at more
clinically relevant doses was performed in order to better characterize
its potential renal effects. The doses of 40, 120, and 200 mg/kg/d were
administered for 1 year. That dose represents 0.8 to 4.0 times the usual
Asacol tablets doses of 2.4 g/d. After one year, also no evidence of drug-related
renal damage was seen.
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