The metabolism and clinical activity of terbutaline and its prodrug ibuterol

Abstract

Ten asthmatic patients received an oral dose of3H-ibuterol chloride 3 mg, which upon hydrolysis generates terbutaline equivalent to 2 mg terbutaline sulphate, and3H-terbutaline sulphate 5 mg, in a double-blind, crossover study with randomized administration. After ibuterol the serum concentration of terbutaline rose steeply and then showed a biphasic decline. The maximum level (4.1 ng/ml) of terbutaline occurred after 30 minutes. After terbutaline there was a slow rise and eight patients showed two peaks in the serum curve. The maximum level of terbutaline, 3.0 ng/ml, occurred after 90 minutes. In both cases the average half-life of terbutaline was 3.4 hours. The absorption of ibuterol was twice as great as that of terbutaline. Due to a slight increase in the degree of conjugation after ibuterol ingestion, the bioavailability of the liberated terbutaline was only about 1.6 that of oral terbutaline. Renal clearance data indicated that terbutaline was filtered only via the glomeruli. The metabolic fate of both drugs was similar, as determined by analysis of urine samples. The same three compounds were found: terbutaline and its sulphate conjugate and glucuronide. The mean maximum increase in FEV1.0 was observed 30 minutes after ibuterol and 90 minutes after terbutaline. No significant effect on circulatory parameters was found after either drug. Tremor was noticed by 2 out of 10 patients after ibuterol and by 4 patients after terbutaline. The results of objective measurements of tremor performed with an accelerometer indicated that the amplitude of tremor had to increase to at least twice its basal value, before the patient was aware of it.