Skin permeation and ex vivo skin metabolism of O-acyl haloperidol ester prodrugs

Ethyl (HE), propyl (HP), butyl (HB), octyl (HO) and decyl (HD) O-acyl esters of haloperidol (HA) were evaluated for permeation across full-thickness human and guinea pig skin. The inclusion of 0.5 mg mL −1 cetrimide as a receptor phase solubilising agent did not significantly alter the barrier prope...

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Bibliographic Details
Published in:International journal of pharmaceutics 2009-02, Vol.367 (1), p.44-50
Main Authors: Morris, Andrew P., Brain, Keith R., Heard, Charles M.
Format: Article
Language:English
Subjects:
Administration, Cutaneous
Animals
Antipsychotic Agents - chemistry
Antipsychotic Agents - pharmacokinetics
Biological Transport
Cetrimide
Drug Stability
Ester
Esters
Female
Guinea Pigs
Haloperidol
Haloperidol - chemistry
Haloperidol - pharmacokinetics
Humans
Hydrolysis
In Vitro Techniques
Liver - metabolism
Male
Molecular Structure
Permeability
Prodrug
Prodrugs - chemistry
Prodrugs - pharmacokinetics
Receptor phase
Skin
Skin - drug effects
Skin - metabolism
Skin Absorption
Solubility
Tissue Extracts - metabolism
Transdermal drug delivery
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Summary:Ethyl (HE), propyl (HP), butyl (HB), octyl (HO) and decyl (HD) O-acyl esters of haloperidol (HA) were evaluated for permeation across full-thickness human and guinea pig skin. The inclusion of 0.5 mg mL −1 cetrimide as a receptor phase solubilising agent did not significantly alter the barrier properties of the membranes. The permeation of the parent drug, HA, across guinea pig skin was found to be greater than that of its derivatives. Prodrug hydrolysis by cutaneous esterases was minimal. The permeation of HE, HP and HB across freshly excised guinea pig skin was subsequently investigated, however, prodrug hydrolysis remained low. Hydrolysis studies using a skin extract revealed only limited prodrug metabolism. However, in the presence of a liver extract, hydrolysis of all prodrugs was rapid. It was proposed that GGGX esterases, required for the hydrolysis of tertiary esters, were not present at a sufficiently high concentration within the skin for substantial prodrug hydrolysis to occur. This does not necessarily detract from the system as post-transdermal delivery liberation of HA in vivo is an equally useful mode for delivering this drug to the systemic circulation.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2008.09.013