BIPHASIC EFFECT-TIME COURSES IN MAN AFTER FORMOTEROL INHALATION - EOSINOPENIC AND HYPOKALEMIC EFFECTS AND INHIBITION OF ALLERGIC SKIN REACTIONS

The kinetics of inhaled racemic formoterol and its effects on the size of the early cutaneous reaction to intradermal injection of an allerg en, eosinopenia and hypokalemia were assessed by pharmacokinetic-pharm acodynamic modeling. After inhalation of either 120 mu g of formoterol or placebo, blood samples were taken and skin tests were performed in seven healthy subjects. A two-compartment model was needed to describ e the observed formoterol plasma concentration-time curves. To describ e the observed biphasic concentration, two absorption routes with diff erent absorption rate constants were incorporated in the model. These two phases were explained by rapid absorption via the respiratory trac t together with a slower and delayed oral absorption. For the descript ion of the concentration-effect relations, an E-max (the maximum obtai nable effect) formula for competitive agonism, with an effect compartm ent, had to be used. Fitting the wheal and flare, an apparent diurnal variation had to be taken into account by incorporating in the model r ising base-line values, For the flare responses, influence of the loca tion on the forearm appeared to be operative. Systemic formoterol abso rbed via the oral route behaved differently from the fraction absorbed via the lungs, with EC50 (steady state concentration that gives 50% o f maximum effect) values for all three systemic effects being three ti mes lower after oral absorption than after absorption via the respirat ory tract. Pharmacodynamic parameters can probably only be estimated q uantitatively when the kinetics of the separate enantiomers of formote rol can be taken into account.