Pharmacokinetics and metabolism of transdermal oxybutynin: in vitro and in vivo performance of a novel delivery system.
OBJECTIVE
The purpose of this work was to characterize in vitro/in vivo delivery and pharmacokinetics of oxybutynin (OXY) and its active metabolite. N-desethyloxybutynin (DEO), by a novel matrix transdermal system (TDS).


METHODS
Two in vivo, randomized, three-way crossover trials examined single/multiple OXY TDS doses. Abdomen, buttock, and hip application sites were compared and dose proportionality was evaluated. Model independent pharmacokinetics, elimination rate constants, and metabolite/drug ratios were derived from both plasma OXY and DEO concentrations.


RESULTS
Single/multiple applications of the OXY TDS to the abdomen yielded mean Cmax OXY concentrations of 3.4 +/- 1.1/6.6 +/- 2.4 ng/mL and median tmax of 36/10 h, with steady state achieved during the second application. Plasma OXY and DEO concentrations decreased gradually after Cmax until system removal. Buttock and hip applications resulted in bioequivalent OXY absorption. AUC ratios of DEO/OXY were 1.5 +/- 0.4 (single dose) and 1.3 +/- 0.3 (multiple dose). Mean in vitro OXY skin absorption (186 microg/h) was comparable to the estimated in vivo delivery (163 microg/h) over 96 h.


CONCLUSIONS
Sustained delivery over 4 days and multiple sites allow a convenient, well-tolerated, twice-weekly OXY TDS dosing. A low incidence of anticholinergic side effects is expected during clinical use because of the avoidance of presystemic metabolism and low DEO plasma concentrations. The consistent delivery, absorption, and pharmacokinetics should result in an effective treatment of patients with overactive bladder.
Zobrist
R Howard
RH
Watson Laboratories, Inc., 417 Wakara Way, Salt Lake City, Utah 84108, USA.
Quan
Danyi
D
Thomas
Heather M
HM
Stanworth
Stephanie
S
Sanders
Steven W
SW
D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016001:Confidence Intervals; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008333:Mandelic Acids / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged
D003692:Delayed-Action Preparations; D008333:Mandelic Acids; C005419:oxybutynin