Safety and absorption of single oral probenecid dose in healthy dogs

Abstract

BACKGROUND: Grape-induced acute kidney injury (AKI) is caused by tartaric acid and may lead to death in dogs. Probenecid, an organic anion transporter-1 inhibitor, recently has been shown to block the uptake of tartaric acid in Madin-Darby canine kidney cells and has been suggested as a possible target for prevention of AKI after grape ingestion. HYPOTHESIS/AIMS: Assess the safety and pharmacokinetics (PK) of PO probenecid in dogs. We hypothesized that probenecid would result in mild, self-limiting gastrointestinal (GI) adverse effects and would be safe in healthy dogs. Additionally, we hypothesized that PO probenecid (50 mg/kg) would have adequate bioavailability and achieve pharmacologically active plasma drug concentrations. ANIMALS: Six healthy beagle dogs. METHODS: Pharmacokinetic (PK) study. Dogs were given 50 mg/kg of probenecid PO, with PK data collected for 48 h after administration. Complete blood count, serum biochemistry profile, urinalysis, and clinical monitoring were performed throughout a 21-day study period to assess safety. Plasma concentration versus time data was analyzed using non-compartmental and two-compartmental modeling. RESULTS: Orally administered probenecid had excellent estimated bioavailability (82.6%) and rapid absorption, with a mean maximal plasma concentration of 589.3 μM (range: 368.0-830.5 μM) within 1.5 h. The mean volume of distribution was 0.71 L/kg, with mean systemic clearance of 0.022 L/h/kg and mean half-life of 24.1 h. Probenecid was well tolerated by all six dogs, with no clinically relevant adverse effects noted. CONCLUSIONS AND CLINICAL IMPORTANCE: Orally administered probenecid is safe and bioavailable in healthy dogs. Future clinical trials assessing PO probenecid in dogs with known tartaric acid ingestion are warranted.