PHARMACODYNAMIC MODELING OF THE DRUG-INDUCED DOWN-REGULATION OF A BETA(2)-ADRENOCEPTOR MEDIATED RESPONSE AND LACK OF RESTORATION OF RECEPTOR FUNCTION AFTER A SINGLE HIGH-DOSE OF PREDNISONE

Changes in beta(2)-adrenoceptor function by chronic dosing of beta(2)- mimetics and the possible influence of a single dose of prednisone hav e been studied as changes over time in the concentration-effect relati onship of the beta(2)-adrenoceptor agonist terbutaline. Hypokalaemia w as used as the specific beta(2)-adrenoceptor mediated effect. 8 health y volunteers were given subcutaneous terbutaline 0.01 mg . kg(-1) BW o n 3 occasions over a 10-day experimental protocol: 1 Control experimen t on Day 1; 2 After 7 days of oral terbutaline 5 mg t.i.d. (Day 8); an d 3 After 8 days on oral terbutaline and 12 h after prednisone 100 mg orally (Day 10). The time course of the terbutaline concentrations and hypokalaemia was related using a pharmacokinetic-pharmacodynamic mode l. A sigmoid and a threshold E(max) model were used to relate drug con centrations to effects. The oral terbutaline treatment caused a 35% in crease in the distribution volume of SC terbutaline. After one week on oral terbutaline the concentration-effect relationship was shifted to the right and was steeper, with a higher EC(50) of terbutaline and hi gher values for the apparent threshold concentration. These observatio ns are compatible with a decrease in receptor numbers after 7 days of terbutaline in a system characterised by the presence of spare recepto rs. The data after prednisone pretreatment showed an apparent decline in the baseline plasma potassium concentrations that could be included in the E(max) model. There was no change in the concentration-effect relationship 12 hours after prednisone.