Plasma concentrations and electrocardiographic alterations after repetitive administration of propoxyphene to dogs

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Propoxyphene hydrochloride was administered orally to four dogs every 8 hr for 19 days. Initial doses of 20 mg/kg were increased to 60 mg/kg in 5 to 15 mg/kg increments every 3 to 4 days. At the conclusion of the experiments animals were ambulatory although signs of toxicity including anorexia, sedation, tremors, and emesis were noted periodically throughout the study. Slight elevations in alkaline phosphatase and serum glutamate pyruvate transaminase values were also observed. Plasma concentrations of propoxyphene (P) (2.3±0.5 μg/ml) and norpropoxyphene (NP) (18.4±4.7 μg/ml), its major metabolite, were markedly elevated over those observed with a single near-lethal dose administered to naive dogs (P, 0.83 μg/ml; NP, 2.56 μg/ml). Tissue concentrations of P and NP were in excess of plasma concentrations showing marked tissue accumulation of both compounds. Electrocardiograms (ECG) showed an increase in PR interval after the first dose of propoxyphene. Doses from 20 to 45 mg/kg produced no further lengthening of the PR interval. Only when dogs were receiving 60 mg/kg (three times daily) were further changes in this interval observed, along with alterations in the QRS complex and T wave portions of the ECG. The average heart rate of these dogs was not significantly altered during the course of the study. At necropsy, mild superficial focal erosions in the mucosa of the stomach and upper small intestine were noted. No other histological changes were observed. These results demonstrated that in the dog, high plasma and tissue concentrations of P and NP can occur without causing significant toxic or lethal effects.