PHARMACOKINETICS OF BAMBUTEROL IN HEALTHY-SUBJECTS

Aims To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjec ts. Methods Eight healthy subjects (four women) received intravenous d oses of bambuterol and terbutaline. On a third occasion, they, plus an other four subjects, ingested oral bambuterol as a single dose followe d by repeated doses once daily for 7 days. Plasma concentrations and u rinary excretion of bambuterol and terbutaline were measured. Results After intravenous administration, renal clearances of bambuterol and t erbutaline were similar (about 140 ml min(-1)), but there was a five-f old difference in total clearance (bambuterol 1.25 l min(-1), terbutal ine 0.23 l min(-1)). Volume of -1 distribution (V-ss) was 1.6 l kg(-1) b.w. for both substances. A similar renal clearance of bambuterol was found during oral administration but that of terbutaline decreased (t o about 120 ml min(-1). Mean terminal half-life of bambuterol was 2.6 h after intravenous and 12 h after oral administration, implying that uptake was rate-limiting. Mean residence time of terbutaline generated from oral bambuterol was 34 h compared with 8.0 h when terbutaline as such was infused. Generated terbutaline had a bioavailability of 36% (28-46) after intravenous and 10.2% (6.1-13.2) after oral administrati on of the prodrug. Bambuterol was well tolerated. The mean activity of plasma cholinesterase, an enzyme catalyzing bambuterol metabolism, wa s inhibited between 30-60% during repeated oral dosing. It virtually r egained original activity within 48 h after the last dose. Conclusions The plasma concentration of terbutaline fluctuated little during repe ated oral administration (mean peak:trough ratio 1.9), as a result of prolonged absorption of bambuterol and slow formation of terbutaline. Thus, the pharmacokinetic properties of bambuterol make it suitable fo r oral once-daily dosage.