Effects of endotoxemia on the pharmacodynamics and pharmacokinetics of ketamine and xylazine anesthesia in Sprague–Dawley rats

Abstract

Purpose:To evaluate the effects of endotoxemia on the pharmacokinetics and pharmacodynamics of ketamine and xylazine anesthesia in Sprague-Dawley rats. Methods: Sprague-Dawley rats received ketamine (80 mg/kg) and xylazine (5 mg/kg) intramuscularly following the intraperitoneal administration of different lipopolysaccharide concentrations (1, 10, and 100 µg/kg) to simulate different levels of endotoxemia. Results were compared to control animals receiving saline intraperitoneally. During anesthesia, a toe pinch was performed to evaluate anesthesia duration, and selected physiological parameters (heart and respiratory rates, oxygen saturation, and rectal temperature) were taken. Blood samples were also taken during anesthesia at selected time points for the analysis of plasmatic ketamine and xylazine concentrations by liquid chromatography-mass spectrometry. Blood samples were taken 1 week prior to and 24 hours following anesthesia for blood biochemistry. Results: Anesthesia duration significantly increased for moderate (10 µg/kg) and high (100 µg/kg) lipopolysaccharide groups. Liver histopathology showed minor to moderate necrosis in all lipopolysaccharide groups in some animals. The most important physiological change that occurred was a decrease in oxygen saturation, and for blood biochemistry a decrease in serum albumin. Ketamine pharmacokinetics were not affected except for the moderate (10 µg/kg) lipopolysaccharide group where a decrease in the area under the plasma concentration-time curve from time zero to the last measurable concentration, a decrease in half-life, and an increase in the clearance were observed. For xylazine, the area under the plasma concentration-time curve increased and the clearance decreased in the moderate (10 µg/kg) and high (100 µg/kg) lipopolysaccharide groups. Conclusion: During ketamine-xylazine anesthesia, endotoxemia may alter xylazine pharmacokinetics and selected biochemical and physiological parameters, suggesting that anesthetic drug dosages could be modified for a more rapid recovery.

Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

“…Acute lipopolysaccharide treatment has been reported to lower plasma ketamine AUC and increase its elimination t1/2, indicating increased BBB permeability and access of ketamine into the brain (Vachon et al, 2012). In repeated administration, morphine may also increase the permeability of the BBB (Sharma and Ali, 2006).…”

Optimisation of ketamine‐xylazine anaesthetic dose and its association with changes in the dendritic spine of CA1 hippocampus in the young and old male and female Wistar rats

“…High doses of xylazine have been shown to likely cause pulmonary oedema and death in Sprague‐Dawley rats (Amouzadeh et al., 1993; Amouzadeh et al., 1991; Kanniappan & Ramaswamy, 1979). Some factors like age and sex can affect drug distribution and pharmacokinetics (Song et al., 2012; Veilleux‐Lemieux et al., 2012). Aging because of subclinical inflammation, obesity and less activity could affect drug metabolism (Mézière et al., 2013).…”