Relative Bioavailability of Metaproterenol in Humans Utilizing a Single Dose, Stable Isotope Approach

Abstract

The relative bioavailability of metaproterenol (3, 5-dihy-droxy-α-[(isopropylamino)methyl]benzyl alcohol) following a single dose (10-mg metaproterenol sulfate tablet) was studied in six normal male volunteers using coadministration of a solution of a deuterated analogue (metaproterenol-d7 sulfate). The bioavailability of the tablet formulation relative to that of the oral solution was 92 ± 9%, with excellent power at the 5% significance level. Comparison of the coadministration of the labeled and unlabeled metaproterenol sulfate solutions in two subjects after a one-week washout demonstrated the absence of an isotope effect on either absorption or elimination. A GC-MS assay for metaproterenol was developed to measure plasma concentrations resulting from oral administration. The assay was linear over the range of 0.5–8ng/mL, corresponding to typical plasma metaproterenol concentrations obtained after a single 10-mg oral dose. Accuracy and precision data were obtained at metaproterenol concentrations of 1.0 and 2.0ng/mL plasma to demonstrate the applicability of the assay for bioavailability studies. Following oral administration, metaproterenol showed peak plasma concentrations of 2.2 to 13ng/mL at 0.75 to 3.0 h, with a terminal harmonic mean half-life of 2.1h over the plasma concentration range studied. The renal clearance of 133–158mL/min for metaproterenol slightly exceeds the glomerular filtration rate in humans.