Labetalol pharmacokinetics and pharmacodynamics: Evidence of stereoselective disposition

Labetalol pharmacokinetics and pharmacodynamics were evaluated in nine subjects before and during enzyme inhibition with Cimetidine. Pharmacologic response was assessed by use of standardized treadmill tests during 24 hours after administration of oral labetalol. Oral clearance of labetalol decreased with Cimetidine administration (58.7 ± 23.3 to 32.9 ± 13.2 ml/min/kg; p < 0.05), thereby causing a 79% increase in area under the curve. Labetalol systemic clearance also decreased (23.2 ± 5.3 to 17.7 ± 3.7 ml/min/kg; p <0.05), but the volume of distribution was unchanged. Labetalol caused significant ß‐blockade for 8 hours after the last oral dose, but Cimetidine did not alter pharmacologic response. The E max model provided a good description of the concentration‐effect relationship. At peak labetalol concentrations after oral administration, (R,R)‐labetalol concentrations were significantly lower than those of the other three stereoisomers ( p < 0.05). Cimetidine caused an increase in the concentrations of each stereoisomer, but the difference was significant ( p < 0.05) for only the (S,R)‐, (S,S)‐, and (R,S)‐isomers. This first evidence of labetalol stereoselective disposition is consistent with the findings of previous (R,R)‐labetalol pharmacokinetic studies and with previous pharmacodynamic investigations of labetalol and (R,R)‐labetalol. Clinical Pharmacology and Therapeutics (1990) 48, 509–519; doi: 10.1038/clpt.1990.187