Influence of debrisoquine oxidation phenotype on exercise tolerance and subjective fatigue after metoprolol and atenolol in healthy subjects.
1. The effects of single doses of metoprolol 50 mg, metoprolol 100 mg and atenolol 100 mg on exercise tolerance were compared with placebo in a double-blind random cross-over study in 12 healthy subjects. Nine subjects were extensive metabolisers of debrisoquine, and three were poor metabolisers. 2. Three hours after dosing beta-adrenoceptor blocker treatments significantly reduced exercise heart rate, prolonged time to complete exercise, and increased subjective fatigue measured by visual analogue scale. 3. Scores for subjective fatigue did not correlate with reduction in exercise heart rate or prolongation of exercise time. Exercise time prolongation was weakly but not significantly correlated with exercise heart rate reduction. 4. When compared with placebo, prolongation of exercise time and increased fatigue with metoprolol were not significantly related to debrisoquine oxidation phenotype or to the debrisoquine/4-hydroxydebrisoquine (D/4OH-D) ratio. 5. When metoprolol responses were compared with those for atenolol, changes in exercise time and fatigue scores were significantly related to oxidation phenotype. For metoprolol 100 mg, poor metabolisers required 20.8 s longer to complete exercise (P less than 0.05) and had higher fatigue scores by 78% (P less than 0.05) as compared with extensive metabolisers.(ABSTRACT TRUNCATED AT 400 WORDS)
Lewis
R V
RV
University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.
Ramsay
L E
LE
Jackson
P R
PR
Yeo
W W
WW
Lennard
M S
MS
Tucker
G T
GT
D000328:Adult; D001262:Atenolol / Q000494:pharmacology*; D003647:Debrisoquin / Q000378:metabolism*; D005221:Fatigue / Q000209:etiology*; D005260:Female; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010641:Phenotype; D010807:Physical Endurance / Q000187:drug effects*
D001262:Atenolol; D008790:Metoprolol; D003647:Debrisoquin