Pulmonary disposition and pharmacodynamics of verapamil

Verapamil, a calcium channel blocker, has received recent attention as a potential therapeutic agent in pulmonary hypertension. Accordingly, 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 efflux of verapamil into drug-free perfusate occurred from two 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 third "noneffluxable" pool. The time course for decline of verapamil inhibition of pulmonary vasoconstriction was compared with the rate of verapamil efflux. Inhibition of pulmonary vasoconstriction was related to the amount of verapamil in a pool exhibiting mono-exponential 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. These findings indicate that the verapamil persists in the lungs in the form of a noneffluxable pool and that verapamil in the pool with half-life of 14.1 min is responsible for some of the vasoactivity in the pulmonary circulation.