The absorption of disopyramide in animals determined using a stable isotope co-administration technique

The stable isotope co-administration technique for estimating the bioavailability of drugs has been investigated in a series of experiments using rhesus monkeys. The compound chosen for study was disopyramide phosphate. A cross-over study was designed whereby the animals received disopyramide phosphate (administered intravenously at 5 mg kg-1) and [13C, 15N]disopyramide phosphate (administered orally at 5 mg kg-1), with a wash-out period between doses. A co-administration study was carried out whereby both the oral and intravenous doses were administered together. The co-administration study was repeated. The results from the cross-over study showed [13C, 15N]disopyramide to have an oral availability of 4.9 +/- 0.9% (by comparing areas under the plasma concentration versus time curves). The bioavailability was estimated to be 5.7 +/- 0.3% comparing totals excreted in urine over 48 h. The bioavailability of the oral dose was calculated as 8.2 +/- 2.5% (comparing areas under plasma concentration versus time curves) and 9.3 +/- 3.0% (comparing totals excreted in urine) after co-administration. The differences between these results and the cross-over results were examined in a further study, using oral administration only. The animals were dosed orally with a solution containing both disopyramide phosphate (5 mg kg-1) and [13C, 15N]disopyramide phosphate (5 mg kg-1). No differences were observed between the plasma concentration versus time curves or urinary excretion for either isotope. It is unlikely that the discrepancy in bioavailability is due to absorption, metabolism or exretion of the oral dose. It is probable that the high concentration of disopyramide obtained after the intravenous dosage affects the disposition of the oral dose, and this gives the higher figure.