Gender-related effects on metoprolol pharmacokinetics and pharmacodynamicsin healthy volunteers

Objective: To determine whether there are gender-specific differences in th e pharmacokinetics and pharmacodynamics of metoprolol enantiomers. Methods: Twenty normal volunteers (10 men and 10 women) received 100 mg ora l metoprolol tartrate twice daily for a total of nine doses. Pharmacokineti cs and pharmacodynamics were studied after the last dose. Subjects also com pleted a control pharmacodynamic study; the order of drug and control studi es was randomized. Measurements of heart rate and systolic blood pressure w ere obtained during peak submaximal bicycle exercise testing. (R)-Metoprolo l and (S)-metoprolol concentrations were determined by stereospecific HPLC, The percentage difference in exercise heart rate and systolic blood pressu re (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentr ations were comodeled, Results: Men and women showed stereoselective pharmacokinetics; (S)-metopro lol concentrations were significantly greater than those for (R)-metoprolol for both groups, Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve), No diffe rences were observed between genders with respect to elimination half-life, Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greate r for heart rate only. Pharmacodynamic data were best fitted by the Kill eq uation with the effect site in the central compartment, The fitted maximum effect and the concentration at one-half of the maximum effect for heart ra te and systolic blood pressure did not differ between men and women (P > .2 0). Conclusions: Gender-related differences exist in the pharmacokinetics of me toprolol enantiomers, resulting in greater drug exposure in female subjects . However, concentration-effect relationships did not differ between men an d women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.