Enantioselective disposition of oral amlodipine in healthy volunteers.
Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the Cmax and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with--and thus highly predictive for--the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers.
Laufen
H
H
Pfizer Mack Research and Development Laboratories, Illertissen, Germany.
Leitold
M
M
D000284:Administration, Oral; D017311:Amlodipine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D018592:Cross-Over Studies; D006207:Half-Life; D006801:Humans; D008102:Liver Circulation; D008657:Metabolic Clearance Rate; D012044:Regression Analysis; D013329:Structure-Activity Relationship
D017311:Amlodipine