Disposition, metabolism, and pharmacodynamics of labetalol in adult sheep.

Labetalol causes significant maternal and fetal metabolic effects in pregnant sheep (Yeleswaram et al., J. Pharmacol. Exp. Ther. 262, 683-691 (1992)). This study was undertaken to investigate the contribution of skeletal muscles in the development of metabolic acidosis induced by labetalol and to explore the involvement of active metabolite(s) using conscious, chronically instrumented adult nonpregnant ewes. Following a 100 mg iv bolus, the disposition of labetalol was similar to that observed in pregnant sheep. The effects of labetalol included hypotension, reflex tachycardia, a significant increase in femoral blood flow, hyperglycemia, lactic acidosis, and increased hind limb oxygen consumption. The arteriovenous flux of labetalol, glucose, lactate, and oxygen across the hindlimb was calculated using the Fick principle. The net output of lactate from the hindquarter over 12 hr following drug administration was calculated to be 6.25 +/- 1.35 g (0.07 +/- 0.015 mol). Glucuronidation, sulfation, and oxidative metabolism of labetalol were studied using urine and bile samples. The cumulative urinary excretion of labetalol as unchanged drug, glucuronide and sulfate was found to be 1.61 +/- 0.3, 11.46 +/- 2.83, and 1.47 +/- 0.74% of the dose, respectively. Using GC-mass selective detection, the presence of 3-amino-1-phenylbutane (3-APB), a close congener of amphetamine, in urine and bile samples was established. The cumulative excretion of 3-APB in urine represents 0.044 +/- 0.016% of the dose. Pharmacokinetic analysis shows the apparent elimination half-life of the metabolite to be 13.5 +/- 3.8 min. Conjugates of 3-APB were also found in the bile and urine.(ABSTRACT TRUNCATED AT 250 WORDS)