TOXICOLOGICAL COMPARISON OF A MUSCARINIC AGONIST GIVEN TO RATS BY GAVAGE OR IN THE DIET

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 wer e investigated. In addition, the muscarinic antagonist scopolamine was co-administered with CI-979 to evaluate the relationship of these eff ects to pharmacological mechanism of action of CI-979. Female rats wer e 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 SO mg/kg body weight for up to 14 days. D ose-related clinical signs of muscarinic stimulation, such as sialorrh oea 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, pyelonephrit is, and inflammation and necrosis of the kidney, urinary bladder, uret hra 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 mor e rapidly and were generally of greater severity when CI-979 was given in the diet. The induction of corneal lesions, as well as urinary sep sis, may not relate simply to maximum plasma concentrations or to area s under the curve per se, but rather may arise when plasma drug concen trations are sustained. Corneal opacification and development of urina ry tract pathology were inhibited by scopolamine, suggesting that thes e effects were related to the muscarinic mechanism of action of CI-979 . (C) 1996 Elsevier Science Ltd. All rights reserved.