Pharmacokinetics, blood and urine profile effects, and injection site histopathology following three daily injections of subcutaneous high concentration buprenorphine in New Zealand white rabbits (Oryctolagus cuniculus)

Abstract

Buprenorphine is a common analgesic administered to rabbits and high concentration formulations can reduce handling stress without sacrificing pain relief. The objective of this study was to evaluate the pharmacokinetics of high concentration buprenorphine and its metabolites following multiple subcutaneous doses in the rabbit. Laboratory variables (complete blood cell count , biochemistry profile, urinalysis) were compared for drug effects and injection sites were evaluated via histopathology. High concentration buprenorphine (HCB) was administered subcutaneously (0.24 mg/kg) to six, 17-week-old, intact female, New Zealand white rabbits ( Oryctolagus cuniculus ) for three doses, 24 hours apart. Two control animals received an equal volume of saline. Blood samples were collected at -72, 0, 0.33, 0.66, 1.5, 3, 6, 12, 24, 48, 72, 96, 120, and 144 hours. Buprenorphine and its metabolites were measured via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). Blood and urine profiles were collected prior to and following HCB administration and compared within and between groups. Injection sites and major organ systems were evaluated grossly and microscopically for drug effects. High concentration buprenorphine administered once every 24 hours for three doses had a variable accumulation index of 1.68 (1.24–2.29), reflecting variability in terminal half-life. Subsequently, the metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide had accumulation indices of 1.79 (1.25–2.77) and 1.84 (1.43–2.88), respectively. No significant laboratory changes were attributed to multiple dose drug administration. Local subcutaneous vasculitis and panniculitis were reported in rabbits receiving HCB. Ante-mortem examination did not find clinical disease, however 6 of 8 rabbits, including controls, had multifocal inflammatory changes in the liver and lungs on histopathology. Subcutaneous high concentration buprenorphine in rabbits has substantial pharmacokinetic variability and accumulation of both the parent drug and metabolites occurs with multiple dosing regimens. Subclinical illness may have impacted these findings and is a notable study limitation. Local inflammation in subcutaneous fat at injection sites was noted in rabbits administered HCB. High concentration buprenorphine has a quick onset of action when administered subcutaneously in the rabbit, but individual variability is notable. Subclinical inflammatory illness may prolong buprenorphine metabolism and clearance and should be considered in determining dosing regimens in rabbits, especially if disease is present or suspected. Inflammation at HCB injection sites is a drug sequela; monitoring injection sites is recommended.