Evaluation of stereoselective transdermal transport and concurrent cutaneous hydrolysis of several ester prodrugs of propranolol: mechanism of stereoselective permeation.
OBJECTIVE
The purpose of this study was to evaluate the stereoselective permeation and concurrent cutaneous hydrolysis of a series of ester prodrugs of propranolol (PL).


METHODS
In vitro studies were performed across full-thickness, stripped and diisopropylfluorophosphate (DFP) treated skins of hairless mouse with flow-through diffusion cells at 37 degrees C.


RESULTS
The permeability coefficients (Kp), which were dependent on partition coefficients (PC), of all the prodrugs were markedly increased compared to the parent drug. In full-thickness skin, the (R) caproyl-PL (CR-PL) showed the highest Kp, which was about 52-fold greater than that of PL. Most of the more lipophilic prodrugs showed stereoselectivity in Kp (R > S). All the prodrugs underwent stereoselective hydrolysis (R > S) during penetration. The prodrugs which showed stereoselectivity in permeation were comparatively lipophilic and showed great differences in hydrolysis percentages between the enantiomers. Permeation studies with stripped skin revealed that prodrugs were more permeable across stratum corneum compared to PL, whereas reverse was happened across viable skin. Although CR-PL showed high stereoselectivity in permeation across full-thickness skin and underwent higher percent of concurrent stereoselective cutaneous hydrolysis, the prodrug showed no stereoselectivity in permeation across DFP, an esterase inhibitor, treated skin and the concurrent cutaneous hydrolysis was also stopped.


CONCLUSIONS
Lipophilic prodrugs may readily pass the stratum corneum but may not be able to penetrate so easily through the deeper tissues. Unlike the (S) isomers, the (R) isomers of lipophilic prodrugs almost completely converted to propranolol in epidermis and can easily pass through the dermis layer, resulting in stereoselective penetration.
Ahmed
S
S
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Imai
T
T
Otagiri
M
M
D000279:Administration, Cutaneous; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004952:Esters / Q000378:metabolism / Q000493:pharmacokinetics; D005069:Evaluation Studies as Topic; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D011433:Propranolol / Q000378:metabolism / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D004952:Esters; D011355:Prodrugs; D011433:Propranolol