Gender differences in labetalol kinetics: Importance of determining stereoisomer kinetics for racemic drugs

Study Objective. To evaluate the impact of gender on labetalol kinetics. Design. Part of a randomized, crossover study. Setting. Academic medical center. Patients. Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whi tes). Interventions. Participants had labetalol dosages titrated to a specific an tihypertensive response, then underwent ambulatory blood pressure monitorin g (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high-performance liquid chromatography (HPLC) and labetalol ste reoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection. Measurements and Main Results. Labetalol concentrations were 80% higher in women (area under the concentration-time curve [AUC]dose.1000: 6.79 +/- 2.1 1 in women vs 3.82 +/- 1.37 hr/L in men, p<0.05), yet both genders had a si milar antihypertensive response by 24-hour ABPM. Dose-corrected AUC (AUC/do se.1000) for labetalol's stereoisomers in women and men, respectively, were S,R-labetalol 7.55 +/- 1.47 and 4.83 +/- 1.54 hr/L (p<0.05), S,S-labetalol 8.23 +/- 2.93 and 4.65 +/- 1.78 hr/L (p<0.05), R,S-labetalol 6.99 +/- 3.30 and 4.25 +/- 2.35 hm (p=0.11), and R,R-labetalol 3.91 +/- 2.57 and 3.55 +/ - 3.08 hm. (NS). Conclusion. The higher labetalol concentration in women than in men was exp lained largely by differences in inactive and alpha(1)-blocking stereoisome rs. However, concentrations were similar between genders for the beta-block ing stereoisomer (R,R-labetalol), possibly explaining the similarity in ant ihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, pa rticularly when relating concentrations to pharmacologic response.