Expression of Carboxylesterase Isozymes and Their Role in the Behavior of a Fexofenadine Prodrug in Rat Skin

Abstract

The expression of carboxylesterase (CES) and the transdermal movement of an ester prodrug were studied in rat skin. Ethyl-fexofenadine (ethyl-FXD) was used as a model lipophilic prodrug that is slowly hydrolyzed to its parent drug, FXD (MW 502). Among the CES1 and CES2 isozymes, Hydrolase A is predominant in rat skin and this enzyme was involved in 65% of the cutaneous hydrolysis of ethyl-FXD. The similarity of the permeation behavior of ethyl-FXD in full thickness and stripped skin indicated that the stratum corneum was not a barrier to penetration. However, only FXD was observed in receptor fluid, not ethyl-FXD, presumably because of the high degree of binding of ethyl-FXD in viable skin. The rate of hydrolysis of ethyl-FXD was much faster than steady-state flux, such that the influx rate was the rate-limiting process for transdermal permeation. Although Hydrolase A levels gradually increased in skin taken from rats aged from 8 to 90 weeks, variations in the expression levels of the esterase hardly affected the conversion of prodrug. The present data suggest that the slow hydrolysis of the prodrug of an active ingredient in viable skin followed by slow diffusion of active drug may provide a useful approach to topical application.

Estimation of human percutaneous bioavailability for two novel brominated flame retardants, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (EH-TBB) and bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP)

“…Skin is a metabolically active organ, with phase I (oxidative metabolism), phase II (conjugative metabolism), and phase III (transport) processes occurring (67-69). Organic anion transporting polypeptide (OATP) proteins have been shown to facilitate increased systemic exposure of PBDEs and other lipophilic chemicals in intestine and liver (70-72).…”

Skin Penetration and Stability Enhancement of Celastrus paniculatus Seed Oil by 2-Hydroxypropyl-β-Cyclodextrin Inclusion Complex for Cosmeceutical Applications

“…Except for rat skin, rodent skin generally shows higher permeation rates than human skin [35,36]. Nevertheless, rat skin was used in the skin-permeation assessment [37][38][39][40]. Moreover, the permeation kinetic parameters are frequently comparable with human skin.…”

Synthesis, Characterization, and Evaluation of Triptolide Cell-Penetrating Peptide Derivative for Transdermal Delivery of Triptolide

“…As previously reported, human esterases are highly active and able to hydrolyze substances extensively during permeation through in vitro human skin, such as 3-alkyl esters of naltrexone and ester derivatives of fluoroxypyr. 36 In addition, rat skin also shows relatively high esterase activity; most of the esterases are located in epidemis and dermis, and the major esterase is carboxylesterase (CES: EC.3.1.1.1). 36 Therefore, the degradation might take place after TP-S-S-CR 7 penetration across the corneum into epidemis and dermis.…”

“…36 In addition, rat skin also shows relatively high esterase activity; most of the esterases are located in epidemis and dermis, and the major esterase is carboxylesterase (CES: EC.3.1.1.1). 36 Therefore, the degradation might take place after TP-S-S-CR 7 penetration across the corneum into epidemis and dermis.…”