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Aims: To study the pharmacokinetics and bioavailability of the prodrug bambuterol and its bronchodilator moiety terbutaline in healthy subjects., Methods: Eight healthy subjects (four women) received intravenous doses of bambuterol and terbutaline. On a third occasion, they, plus another four subjects, ingested oral bambuterol as a single dose followed by repeated doses once daily for 7 days. Plasma concentrations and urinary excretion of bambuterol and terbutaline were measured., Results: After intravenous administration, renal clearances of bambuterol and terbutaline were similar (about 140 ml min(-1)), but there was a five-fold difference in total clearance (bambuterol 1.25 l min(-1), terbutaline 0.23 l min(-1)). Volume of distribution (Vss) 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 (to 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 administration of the prodrug. Bambuterol was well tolerated. The mean activity of plasma cholinesterase, an enzyme catalyzing bambuterol metabolism, was inhibited between 30-60% during repeated oral dosing. It virtually regained original activity within 48 h after the last dose., Conclusions: The plasma concentration ofterbutaline fluctuated little during repeated 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 for oral once-daily dosage.

The absorption of the two enantiomers of terbutaline, (+)-terbutaline and (-)-terbutaline, and of the racemate, (+/-)-terbutaline, has been studied in six healthy volunteers using a newly developed intestinal perfusion technique. The area under the plasma concentration curve for the (-)-enantiomer was more than twice that for the (+)-enantiomer. The data demonstrate a clear difference in absorption efficiency between (-)- and (+)-terbutaline, but further studies are required to establish whether (-)-terbutaline influences the absorption of (+)-terbutaline.

The purpose of this work was to develop and validate a method for the separation and determination of the enantiomers of terbutaline in plasma and intestinal juice. Terbutaline was extracted from plasma and intestinal juice by liquid-solid extraction on small C18 cartridges. The extract was then analyzed by coupled column liquid chromatography with amperometric detection. For chiral separation a beta-cyclodextrin phase was used. The within-day variation (Cv) on spiked plasma samples was in the range 0.8-6.4% at 3.8-33.8 nmol/liter for the (-)-enantiomer, and 2.6-23.0% at 1.3-11.3 nmol/liter for the (+)-enantiomer. The between-day variation on spiked plasma samples was 5.5% at 10.7 nmol/liter and 13.6% at 4.3 nmol/liter for the (-)-and (+)-enantiomers, respectively. The within-day variation for intestinal juice was in the range 0.7-1.5% at 5.6-30.0 mumol/liter for the (+)-enantiomer.

Three pharmacokinetic studies of terbutaline slow-release (SR) tablets, 5 and 7.5 mg, were performed in healthy subjects. Four men and 4 women volunteered for each study. Bricanyl plain tablets were used as reference formulation. Both single- and multiple-dose treatments were performed. For repeated administration, SR tablets were given every 12 h. Plain tablets were given every 8 h in two studies and every 12 h in one. Steady-state bioavailability correlated with the amount dissolved in vitro (paddle method) in 6 h. Single-dose bioavailability was limited by the amount dissolved in 4 h. The difference may have a pharmacological explanation, in that repeated administration of a sympathomimetic drug is known to decrease gastro-intestinal motility. Tablets of both strengths with an intermediate dissolution rate were extensively tested. Plasma concentrations and the rates of urinary excretion of unchanged terbutaline were measured. Mean relative bioavailability compared with plain tablets was 76-77% with 7.5 mg SR tablets and 74-80% with those of 5 mg. Variation in bioavailability between and within subjects was the same or smaller with the SR tablets. They gave smoother plasma concentration profiles with delayed peaks and the same peak/trough concentration ratios as the plain tablets, despite less frequent dosing. However, objectively measured side-effects were not significantly reduced. Measurements after cessation of treatment gave terminal half-lives in plasma of 11.5-23.0 h which is considerably longer than reported in the literature. Renal clearance averaged 140 mL/min, similar to predicted creatinine clearance. From these studies it is concluded that the main advantage with the SR tablets is the twice-daily dosage regimen. This should increase compliance, facilitate combination therapy with prolonged-action formulations of other drugs and better maintain therapeutic levels during the whole night interval.

Because of low drug concentrations and complex nature of the sample, analytical methods with sensitive and selective detection are necessary for pharmacokinetic studies of terbutaline. Up to now, for non-radiolabelled drugs, usually only methods based on gas chromatography plus mass spectrometry have met these requirements. As an alternative, we have developed an automated method based on liquid chromatography. The necessary sensitivity and selectivity were obtained by using electrochemical detection and a microprocessor-controlled column switching system. The accuracy of the method was compared with a method based on gas chromatography plus mass spectrometry. The overall precision expressed as per cent of the mean was +/- 3.5% and +/- 2.2% at 5 and 50 pmol/mL, respectively. The total absolute recovery for terbutaline and internal standard at these concentration levels were in the range 85-106%.