Pharmacokinetics of the R- and S-enantiomers of oxybutynin and N-desethyloxybutynin following oral and transdermal administration of the racemate in healthy volunteers.
OBJECTIVE
To characterize the enantiomers of oxybutynin (OXY) and N-desethyloxybutynin (DEO) following transdermal and oral administration.


METHODS
OXY was administered either as a single transdermal system over a 96 h wear period or as a single 5 mg immediate-release tablet to 18 healthy male and female subjects in a randomized, open-label, two-way crossover design. Blood samples were collected for 108 h after application of the transdermal system and for 6 h after oral administration. Plasma concentrations of the R- and S-enantiomers of OXY and DEO were assayed by LC-MS/MS. Enantiomer in vitro skin flux was evaluated using human cadaver skin.


RESULTS
In vitro skin flux studies demonstrated equal absorption of R and S- OXY. Plasma concentrations and pharmacokinetic parameters of the R-enantiomers of OXY and DEO were slightly lower than the S-enantiomers following transdermal OXY. The relative AUC values were S-OXY>S-DEO>R-OXY>R-DEO. The AUC ratios of DEO/ OXY were less than 1 for both the R- and S- enantiomers. Following oral dosing, plasma DEO concentrations greatly exceeded OXY resulting in relative AUC values of R-DEO>S-DEO>S-OXY>R-OXY. The mean AUC ratios of S- and R-DEO/OXY were 3.25 and 8.93, respectively.


CONCLUSIONS
Stereoselective metabolism of OXY was evident following both transdermal and oral administration of OXY. The reduced pre-systemic metabolism of transdermally administered OXY compared to oral administration resulted in not only significantly lower DEO plasma concentrations, but also a different metabolite pattern. The differences between R-OXY and R-DEO following the two routes of administration support the potential for comparable clinical efficacy and reduced anticholinergic side-effects with transdermal treatment.
Zobrist
R H
RH
Watson Laboratories, Inc, Salt Lake City, Utah 84108, USA. hzobrist@watsonpharm.com
Schmid
B
B
Feick
A
A
Quan
D
D
Sanders
S W
SW
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008297:Male; D008333:Mandelic Acids / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D010276:Parasympatholytics / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D012869:Skin Absorption / Q000502:physiology; D013237:Stereoisomerism
D008333:Mandelic Acids; D010276:Parasympatholytics; C032681:desethyloxybutynin; C005419:oxybutynin