Subcutaneous and orally self-administered high-dose carprofen in male and female mice: pharmacokinetics, tolerability and impact on cage-side pain indicators

Abstract

Surgical interventions in mice are prerequisite in various research fields and require appropriate pain relief, not only to ensure animal welfare but also to avoid influence of pain on research findings. Carprofen is a non-steroidal anti-inflammatory drug that is commonly used as an analgesic for interventions inducing mild to moderate pain in animals. Despite its frequent use also in laboratory rodents, data on pharmacokinetics and side effects, and on its potential impact on behavioral pain indicators are rare. This study aimed to determine pharmacokinetic and tolerability profiles of high dose carprofen in male and female C57Bl/6J mice, administered via single subcutaneous injection (s.c.) and oral self-administration per drinking water (d.w.). Plasma concentrations of carprofen were measured at various time points, and side effects were evaluated using a modified Irwin test protocol, hematology and histopathology. Additionally, potential effects on behavioral pain indicators commonly used to assess post-surgical pain, such as the mouse grimace scale, wheel running activity, burrowing, nesting and grooming behavior were investigated. Quantification of carprofen in plasma revealed maximum plasma concentrations of 133.4 +/- 11.3 microgram/ml after 1 hour and an elimination half-life of 8.52 hour after single s.c. injection of 20 mg/kg carprofen. Oral self-administration of carprofen (25 mg/kg/24 h) resulted in a steady-state < 24 hours over 5 days after treatment start with plasma levels of around 60 microgram/ml. The carprofen-medicated water was highly accepted, and increased d.w. intake was observed in the first 24 hours after exposure for both sexes (p < 0.0001). Irwin test detected only minor side effects, and hematology and histopathology where without pathological findings that could be attributed to carprofen treatment. Except for a decrease of 49-70 % in wheel running activity in male mice, behavioral pain indicators were only very mildly affected. This study determined carprofen plasma levels in mice lying well above an estimated therapeutic concentration for both routes of administration. Carprofen was well tolerated at recommended high doses and may provide sufficient analgesia for minor interventions as well as be applied as a tolerable component in multimodal analgesic regimens.