Mesalazine: an overview of key preclinical studies.

Studies were undertaken to evaluate the clinical relevance of toxicologic assessments of mesalazine and to establish mesalazine pharamcokinetics. In the toxicology studies groups of rats and dogs received various doses of mesalazine, ranging from 40 to 320 mg/kg of body weight, for 6 or 12 months. Evidence of renal papillary necrosis was found at 60 or 100 mg/kg in dogs and 320 mg/kg in rats. Data are presented to show that drug absorption after the clinical doses of mesalazine given to human patients is much lower than after the potentially nephrotoxic doses given to experimental animals. In the pharmacokinetic studies plasma from rats and dogs given various doses of mesalazine was analysed for mesalazine and its major metabolites. The results demonstrated that mesalazine in pharmaceutic preparations is not likely to present a nephrotoxic risk to patients, given the low systemic exposure achieved. After 12 months of mesalazine administration to dogs, many showed an ocular condition diagnosed as keratoconjunctivitis sicca. Experimental and epidemiologic evidence demonstrates that this condition is peculiar to dogs, and there are no reports of untoward ocular effects in patients receiving long-term therapy with mesalazine.