A pharmacological method to estimate the pK I of competitive inhibitors of agonist uptake processes in isolated tissues

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Abstract
An equation is derived from a mathematical model (proposed by Furchgott) which, under certain circumstances, estimates the pK I (-log dissociation constant) of a competitive inhibitor of agonist uptake by utilizing the sensitization of isolated tissues, to the substrate-agonist, by uptake inhibition. The method is theoretically more sound and appears to be improved by the use of potency-ratios of the substrate-agonist and an agonist which is not a substrate for the uptake process since this allows for the detection and correction of receptor and toxic effects of uptake inhibitors. The pK I values of cocaine, desmethylimipramine and imipramine for the neuronal uptake of norepinephrine were estimated by this method in guinea-pig tracheae and left atria. Also, the pK I values for 17 β-oestradiol, corticosterone, clonidine and metanephrine for the extraneuronal uptake of isoproterenol were estimated in guinea-pig tracheae (and cat left atria for 17 β-oestradiol). All estimates were consistent with literature pK I values obtained biochemically with radiolabelled substrates.

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