Pharmacokinetics and relative bioavailability of D-penicillamine in fasted and nonfasted dogs.

Abstract

BACKGROUND: D-Penicillamine is the most commonly used copper-chelating agent in the treatment of copper-associated hepatitis in dogs. Response to therapy can be variable, and there is a lack of pharmacokinetic information available for dogs. Coadministering the drug with food to alleviate vomiting has been recommended for dogs, which contradicts recommendations for drug administration to humans. HYPOTHESIS: Coadministration of d-penicillamine with food decreases relative bioavailability and maximum plasma drug concentrations (C(max)) in dogs. ANIMALS: Nine purpose-bred dogs with a median body weight of 17.0 kg. METHODS: Dogs received D-penicillamine (12.5 mg/kg PO) fasted and with food in a randomized, crossover design. Blood samples were collected before and 0.25, 0.5, 1, 2, 3, 4, 8, 12, and 24 hours after dosing. Total d-penicillamine concentrations were measured using liquid chromatography coupled with tandem quadrupole mass spectrometry. Pharmacokinetic parameters were calculated for each dog. RESULTS: Two fasted dogs (22%) vomited after receiving d-penicillamine. Mean C(max) &#xb1; standard deviation (SD) was 8.7 &#xb1; 3.1 &#x3bc;g/mL (fasted) and 1.9 &#xb1; 1.6 &#x3bc;g/mL (fed). Mean area under the plasma concentration curve &#xb1; SD was 16.9 &#xb1; 5.9 &#x3bc;g/mL&#xb7;h (fasted) and 4.9 &#xb1; 3.4 &#x3bc;g/mL&#xb7;h (fed). There were significant reductions in relative bioavailability and C(max) in fed dogs (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Coadministration of d-penicillamine with food significantly decreases plasma drug concentrations in dogs. Decreased drug exposure could result in decreased copper chelation efficacy, prolonged therapy, additional cost, and greater disease morbidity. Administration of d-penicillamine with food cannot be categorically recommended without additional studies.