Corneal opacities and urinary tract
sepsis were previously observed by the authors in rats given
muscarinic agonists mixed in the diet or by gavage. To explain the differential toxicity generated by each means of administration, toxicokinetics of the
muscarinic agonist CI-979 were investigated. In addition, the
muscarinic antagonist scopolamine was co-administered with
CI-979 to evaluate the relationship of these effects to pharmacological mechanism of action of
CI-979. Female rats were given
CI-979 daily by gavage at 0, 1, 10 and 30 mg/kg
body weight or in the diet at 0, 1, 10 and 50 mg/kg
body weight for up to 14 days. Dose-related clinical signs of
muscarinic stimulation, such as sialorrhoea and dacryorrhoea, were observed predominantly in rats given 10 and 30 mg/kg
body weight CI-979 by gavage, and corresponded with the high plasma
drug concentrations. In contrast,
hydronephrosis,
pyelonephritis, and
inflammation and
necrosis of the kidney, urinary bladder, urethra and urinary papilla were linked to sustained, albeit lower plasma
drug concentrations attained by dietary administration of
CI-979 at 10 and 50 mg/kg
body weight. Comparable incidences of
corneal opacities were induced by both means of administration, but lesions appeared more rapidly and were generally of greater severity when
CI-979 was given in the diet. The induction of corneal lesions, as well as urinary
sepsis, may not relate simply to maximum plasma concentrations or to areas under the curve per se, but rather may arise when plasma
drug concentrations are sustained. Corneal opacification and development of urinary tract pathology were inhibited by
scopolamine, suggesting that these effects were related to the
muscarinic mechanism of action of
CI-979.