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 0.5mgmL(-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.
Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3NB, UK.
Andrew P
AP
Morris
Keith R
KR
Brain
Charles M
CM
Heard
D000279:Administration, Cutaneous; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D004355:Drug Stability; D004952:Esters; D005260:Female; D006168:Guinea Pigs; D006220:Haloperidol / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D010539:Permeability; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012869:Skin Absorption; D012995:Solubility; D014020:Tissue Extracts / Q000378:metabolism
D014150:Antipsychotic Agents; D004952:Esters; D011355:Prodrugs; D014020:Tissue Extracts; D006220:Haloperidol