Stereoselective pharmacokinetics of oxybutynin and N-desethyloxybutynin in vitro and in vivo

In vitro studies and the multiple applications of an oxybutynin (OXY) transdermal delivery system to Japanese healthy volunteers were conducted to characterize the stereoselectivity in the pharmacokinetics of OXY and its metabolite, N-desethyloxybutynin (DEOB). In human liver microsomes, (R)-OXY and...

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Bibliographic Details
Published in:Xenobiotica 2007-01, Vol.37 (1), p.59-73
Main Authors: Mizushima, H., Takanaka, K., Abe, K., Fukazawa, I., Ishizuka, H.
Format: Article
Language:English
Subjects:
Administration, Cutaneous
Adult
Cytochrome P-450 Enzyme System - metabolism
Female
Humans
Kinetics
Male
Mandelic Acids - blood
Mandelic Acids - chemistry
Mandelic Acids - pharmacokinetics
Mandelic Acids - pharmacology
metabolic study in microsomes
Microsomes, Liver - drug effects
Microsomes, Liver - enzymology
N-desethyloxybutynin
Oxybutynin
Parasympatholytics - blood
Parasympatholytics - chemistry
Parasympatholytics - pharmacokinetics
Parasympatholytics - pharmacology
Protein Binding - drug effects
Stereoisomerism
stereoselectivity
transdermal delivery system
unbound fraction
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Summary:In vitro studies and the multiple applications of an oxybutynin (OXY) transdermal delivery system to Japanese healthy volunteers were conducted to characterize the stereoselectivity in the pharmacokinetics of OXY and its metabolite, N-desethyloxybutynin (DEOB). In human liver microsomes, (R)-OXY and (R)-DEOB were eliminated slightly slower than the corresponding (S)-enantiomers. The production of DEOB from OXY for the (R)-enantiomer was also slower than that for the (S)-enantiomer. In human P450-expressing liver microsomes, OXY was metabolized mainly by CYP3A4 among five cytochrome P450s (CYPs) tested (CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5) and the kinetics were slightly different for the enantiomer. The unbound fraction of (R)-OXY in plasma was almost two times higher than that of (S)-OXY, whereas (R)-DEOB was bound to plasma protein more than (S)-DEOB. No differences were observed in the blood-plasma concentration ratios for the enantiomers. After multiple applications of the transdermal delivery system, the plasma concentrations of (R)-OXY were lower than those of (S)-OXY. These data indicate that for the stereoselectivity of OXY, the unbound fraction of each OXY enantiomer was a major factor and the metabolism in liver had a minimal effect.
ISSN:0049-8254
1366-5928
DOI:10.1080/00498250600976088