Stereoselective pharmacokinetics of oral felodipine and nitrendipine in healthy subjects: correlation with nifedipine pharmacokinetics.
The pharmacokinetics of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all given as an oral dose of 20 mg in solution) have been investigated in a randomised cross-over study in 12 healthy male subjects using stereoselective assays. Both felodipine and nitrendipine exhibited stereoselective pharmacokinetics. On average, the AUCs of the active (S)-enantiomers of felodipine and nitrendipine were 139% and 104% higher than those of their optical antipodes, but the elimination half-lives of the enantiomers of each racemate were not different. The AUCs of nifedipine, rac-felodipine, rac-nitrendipine and of their enantiomers were highly correlated (all r > 0.83), suggesting closely related rate limiting steps in the in vivo first-pass metabolism of these high-clearance drugs. Stereoselectivity was only a minor contributor to inter-individual variability in the oral pharmacokinetics of these compounds in healthy subjects.
Soons
P A
PA
Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
Mulders
T M
TM
Uchida
E
E
Schoemaker
H C
HC
Cohen
A F
AF
Breimer
D D
DD
D000284:Administration, Oral; D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D004311:Double-Blind Method; D015736:Felodipine / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D009543:Nifedipine / Q000097:blood / Q000493:pharmacokinetics*; D009568:Nitrendipine / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000378:metabolism; D013237:Stereoisomerism
D001798:Blood Proteins; D011725:Pyridines; D009568:Nitrendipine; D009543:Nifedipine; D015736:Felodipine