Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.
OBJECTIVE
To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers.


METHODS
Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled.


RESULTS
Men and women showed stereoselective pharmacokinetics; (S)-metoprolol 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 differences 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 greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20).


CONCLUSIONS
Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.
Luzier
A B
AB
Department of Medicine, Millard Fillmore Hospital, and the School of Pharmacy, University at Buffalo, State University of New York, USA. luzier@acsu.buffalo.edu
Killian
A
A
Wilton
J H
JH
Wilson
M F
MF
Forrest
A
A
Kazierad
D J
DJ
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000704:Analysis of Variance; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects*; D015444:Exercise; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D012727:Sex Characteristics; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D008790:Metoprolol