The pharmacokinetics of penicillamine in a female mongrel dog

The pharmacokinetic parameters of D-penicillamine were investigated by administering four intravenous bolus doses, four oral doses, and six constant rate intravenous infusions to a female mongrel dog at dosages comparable to 250, 500, 750, and 1000 mg in man. The pharmacokinetics of D-penicillamine demonstrated nonlinearity in the dog. There was more than proportional increase in the area under the whole blood concentration curve for an increase in the bolus intravenous dose. The steady state whole blood, plasma, and packed cells levels of penicillamine were increased more than proportionately for an increase in the intravenous infusion rate. Total body clearance of penicillamine was decreased by increasing the dose or the infusion rate of penicillamine. Correspondingly, the estimated half-life of unchanged penicillamine in the whole blood was decreased for increased intravenous bolus doses. The renal clearance of penicillamine was nonlinear, decreasing with time during the bolus experiments and increasing at higher infusion rates. The nonrenal clearance was decreased at higher infusion rates, suggesting that a saturable nonrenal elimination process exists for penicillamine in the dog. The nonlinearities that were observed in the dog, if also present in man, may be responsible in part for the dose related side effects reported clinically for penicillamine.