Pulmonary Disposition and Pharmacodynamics of Verapamil

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Abstract
Verapamil, a Ca channel blocker, has received recent attention as a potential therapeutic agent in pulmonary hypertension. The pulmonary disposition and pharmacodynamics of verapamil were evaluated in isolated rat lungs perfused at a constant rate with a physiological salt solution. Isolated rat lungs sequestered but did not metabolize verapamil. The verapamil efflux into drug-free perfusate occurred from 2 kinetically distinct pools with half-lives of 1.3 and 14.1 min. The theoretical amount of verapamil effluxed at infinite time was less than the amount taken up during the infusion, thereby suggesting that verapamil was also bound in a 3rd noneffluxable pool. The time course for decline of verapamil inhibition of pulmonary vasoconstriction was compared with the rate of verapamil efflux. Pulmonary vasconstriction inhibition was related to the amount of verapamil in a pool exhibition monoexponential efflux of drug with a half-life of 12.6 min. This half-life suggests association of the inhibitory response with the efflux component having a half-life of 14.1 min. The verapamil apparently persists in the lungs in the form of a noneffluxable pool. Verapamil in the pool with half-life of 14.1 min is responsible for some vasoactivity in the pulmonary circulation.