Physiological,pharmacokinetic and liver metabolism comparisons between 3-, 6-, 12- and 18-month-old male Sprague Dawley rats under ketamine-xylazine anesthesia

The main objective of this study was to compare the physiological changes (withdrawal andcorneal reflexes, respiratory and cardiac frequency, blood oxygen saturation, and rectaltemperature) following intraperitoneal administration of ketamine (80 mg/kg) and xylazine(10 mg/kg) to 3-, 6-, 12- and 18-month-old male Sprague Dawley rats (n=6/age group).Plasma pharmacokinetics, liver metabolism, and blood biochemistry were examined for alimited number of animals to better explain anesthetic drug effects. Selected organs werecollected for histopathology. The results for the withdrawal and corneal reflexes suggesta shorter duration and decreased depth of anesthesia with aging. Significant cardiac andrespiratory depression, as well as decreased blood oxygen saturation, occurred in all agegroups however, cardiac frequency was the most affected parameter with aging, since the6-, 12-, and 18-month-old animals did not recuperate to normal values during recovery fromanesthesia. Pharmacokinetic parameters (T_1/2 and AUC) increased and drugclearance decreased with aging, which strongly suggests that drug exposure is associatedwith the physiological results. The findings for liver S9 fractions of 18-month-old ratscompared with the other age groups suggest that following a normal ketamine anestheticdose (80 mg/kg), drug metabolism is impaired, leading to a significant increase of drugexposure. In conclusion, age and related factors have a substantial effect on ketamine andxylazine availability, which is reflected by significant changes in pharmacokinetics andliver metabolism of these drugs, and this translates into shorter and less effectiveanesthesia with increasing age.