Mass balance and metabolism of [(3)H]Formoterol in healthy men after combined i.v. and oral administration-mimicking inhalation.

Mass balance and metabolism of formoterol were investigated in six healthy men in an open study. Mean age was 49.7 years (range: 40-63). Simultaneous oral (mean dose 88.6 nmol, 49.3 MBq) and i.v. (mean dose 38.2 nmol, 21.4 MBq) doses of tritium-labeled formoterol were administered. The combination of these two administrations was aimed at simulating the fate of inhaled formoterol. Total radioactivity was monitored for 24 h in blood plasma and for at least 4 days in urine and feces. Formoterol and metabolites were determined using liquid chromatography plus radiodetection, directly after centrifugation in urine and after sample workup in blood plasma and feces. Metabolites were identified in urine, sampled from two subjects, using liquid chromatography-electrospray ionization mass spectrometry. Mean total recovery was 86% of the administered formoterol dose, 62% in urine and 24% in feces. Tritiated water was generated and because its in vivo turnover is slow, the terminal decline of total radioactivity was slow and dose recovery was incomplete during the sampling period. Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low. O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7. 0% in urine and 2.0% in feces.

Oral administration of terbutaline in asthmatic patients.

The absorption and excretion profiles of orally administered terbutaline were investigated in 10 asthmatic patients who received a solution containing 5 mg of [3H]terbutaline sulphate. Bronchodilating effect and side-effects were followed. The mean serum concentration curve reached its maximum of 3.0 +/- 0.3 (SEM) ng/mL at 60-90 min. Renal clearance data indicated that terbutaline was excreted only via glomerular filtration. Approximately 30% of the dose was excreted in the urine in 12 h and 40% in 72 h. Three compounds appeared in the urine: unchanged terbutaline, a sulphate conjugate, and a glucuronide, the main metabolite being the sulphate conjugate. The maximum mean increase in volume of air expelled in the first second of forced expiration (FEV1) was 35%, attained 90-120 min after intake of terbutaline. There was a correlation (r = 0.74) between the serum level and the bronchodilator effect. No significant effects on heart rate or blood pressure were found. Tremor, as objectively measured with the aid of an accelerometer, was experienced by the patients when it increased to twice its basal level. The observed tremor did not appear to parallel either the serum level or the bronchodilating effect. A comparative study in 3 of the patients showed that [3H]terbutaline formulated as a tablet had similar bioavailability.

Assay of tritium-labelled terbutaline.

A method for the determination of unchanged 3H-labelled terbutaline in biological samples was developed for use in early pharmacokinetic investigations involving various species. Terbutaline was isolated from the biological sample by ion pair extraction with 0.015 mol/L bis(2-ethylhexyl)phosphoric acid in methylene chloride. To eliminate co-determination of conjugated terbutaline present in the samples, extraction was combined with partition chromatography. Quantification was achieved by liquid scintillation counting. The recovery of [3H]terbutaline from serum and urine was 96.1 +/- 0.7 (mean +/- SEM) in the concentration range 1-250 ng/mL.

Elimination pathways of terbutaline.

The main elimination pathways of tritium-labelled terbutaline have been investigated in the rat, the dog, and man. In the rat, 25% of an intravenous dose is excreted unchanged in the urine. Terbutaline is extensively metabolized to the glucuronic acid conjugate which is eliminated via bile (40% of the dose) and urine (25% of the dose). After oral administration, a high first-pass metabolism (70%) was found. In contrast, in the dog, more than 90% of a parenteral dose is excreted renally, largely as unchanged terbutaline together with a small amount of the sulphate conjugate. Only 1.7% of the dose is excreted via bile. The first-pass metabolism amounted to 13%. The elimination of terbutaline in man exhibits a pattern intermediate between rat and dog. Thus, more than 90% of a parenteral dose is eliminated in the urine, of which about 2/3 is unchanged drug. The main metabolite is the sulphate conjugate which is excreted renally. Less than 1% of the dose is excreted in the bile. A large first-pass metabolism (69%) was confirmed in man.

Protein binding of enprofylline.

The protein binding of enprofylline, 3-propylxanthine, in plasma was studied by equilibrium dialysis and ultrafiltration under various experimental conditions. A limited comparison with theophylline was also undertaken. The mean fraction of enprofylline bound in human plasma at 20 degrees C was 47.3 +/- 1.1% (SD), which was only 2% less than theophylline. The binding of the two drugs increased dramatically in the pH range 7.2 to 7.8, as reported previously for theophylline. Reasonable agreement was found between equilibrium dialysis and ultrafiltration, but the latter technique proved impractical, because pH control was difficult to achieve. A pronounced species difference in the binding of enprofylline was found. At pH 7.4 an almost constant level of binding of 57% in dog and 81% in rat was found up to 2.10(-5) M (approx. 4 mg/l). Corresponding values in human and monkey plasma were 47 and 48%, respectively, up to 10(-4) M (approx. 20 mg/l).