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Pharmacokinetics of PD123,497, a novel antiarrhythmic drug : early distribution phase in blood and tissues

University of British Columbia

PDI 23,497 is a novel antiarrhythmic drug and the (+) enantiomer of PDII7,302, a kappa (κ) opioid agonist. Using a method of liquid-liquid chemical extraction and high performance liquid chromatography, the pharmacokinetics of PD123,497 in the rat were determined. Specifically, concentration-vs-time profiles were constructed reflecting the early distribution phase of an intravenous bolus dose of 8 µmol/kg in whole blood, heart, liver, brain, and skeletal muscle. The pharmacokinetic data for heart and blood correlated well with the time course of heart rate and blood pressure effects as determined in previous pharmacological assays. The data also correlated well with pharmacological screens in dogs and baboons indicating that the rat model is demonstrative of the situation in other species. Skeletal muscle data indicated a significant capacity for drug accumulation in the muscle beds. Liver data indicated slow uptake and storage of parent drug. Termination of therapeutic effect appeared to be the result of redistribution into other tissues and not metabolism or elimination. Concentrations in the heart were several times higher than that of the blood immediately after administration of drug via the tail vein. This suggests a potential for alpha-phase toxicity. Brain data showed that peak concentration was achieved after that in the heart indicating redistribution from the heart and suggesting that PD123,497 may be able to produce significant CNS side effects.

Thesis/Dissertation

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2009-03-05

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http://hdl.handle.net/2429/5568

Pharmacology and Therapeutics

University of British Columbia

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