Evaluation of the Safety and Pharmacokinetics of Single-Dose Oral Probenecid Administration in Healthy Dogs

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.