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 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.
Dethloff
L A
LA
Department of Pathology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA.
Chang
T
T
Courtney
C L
CL
D000818:Animals; D003315:Cornea / Q000187:drug effects; D004032:Diet; D004095:Dihydropyridines / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007441:Intubation, Gastrointestinal; D015877:Miosis / Q000139:chemically induced; D018721:Muscarinic Agonists / Q000008:administration & dosage* / Q000633:toxicity*; D010091:Oximes / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000008:administration & dosage / Q000494:pharmacology; D012798:Sialorrhea / Q000139:chemically induced; D014554:Urination / Q000187:drug effects
D004095:Dihydropyridines; D018721:Muscarinic Agonists; D010091:Oximes; D012601:Scopolamine; C084978:milameline