The metabolism of debrisoquine in rat and man.

Addition, together with antigen, of compound I.C.I. 74917 (0.1 pg/ml) to chopped sensitized lung, preincubated with DL-isoprenaline for 3 min, resulted in extra inhibition of histamine release as seen in Fig. 2(a). Comparison of the total inhibition with individual values for compound I.C.I. 74917 and isoprenaline show that there is addition rather than synergism, i.e. if compound I.C.I. 74917 inhibits release by y % then isoprenaline could only act on the remaining (1OO-y)% and inhibit it by x% and vice versa (Fig. 2b). It has been shown that compound I.C.I. 74917 is an inhibitor of cyclic AMP phosphodiesterasefromrat mast cells (Barrett-Bee & Henderson, 1976). At theconcentrations used here, however, which were much less than the K, for mast-cell phosphodiesterase, the data indicate that compound I.C.I. 74917 was not acting as a phosphodiesterase inhibitor and potentiating the inhibition by isoprenaline, but it was merely adding to it, i.e. it was acting by a different mechanism. The experiments shown in Fig. 2 demonstrate that the inhibitions of allergic histamine release by compound I.C.I. 74917 and isoprenaline are independent of each other. This would not be expected if compound I.C.I. 74917 was acting as a phosphodiesterase inhibitor. Any inhibition of histamine release by isoprenaline, caused by its increasing the concentration of cyclic AMP by stimulation of the adenyl cyclase, would be potentiated by the presence of a phosphodiesterase inhibitor. Since potentiation does not occur with compound I.C.I. 7491 7, it seems unlikely, therefore, that the anti-allergic properties of compound I.C.I. 74917 involve its activity as an inhibitor of cyclic AMP phosphodiesterase. Disodium cromoglycate, which itself at a concentration of 5OOpg/ml caused no inhibition of histamine release, increased the total inhibition by isoprenaline (Fig. 2a). This suggests that, at high concentrations, poor phosphodiesterase inhibitors such as cromoglycate are able to potentiate the inhibition of histamine release by isoprenaline. However, their normal mode of anti-allergic action does not depend upon this property. Further evidence for this belief is provided by the experiments that indicate that the time ofaddition ofcompound I.C.I. 74917 or disodiumcromoglycaterelative to addition of antigen is critical (Fig. lb). Maximal inhibition is observed when the compound is added with antigen rather than before, as with isoprenaline or theophylline. This observation would indicate that a build-up of cyclic AMP is not required for compound I.C.I. 74917 to inhibit histamine release.