Metabolism of captopril carboxyl ester derivatives for percutaneous absorption.
OBJECTIVE
To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril.


METHODS
The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism).


RESULTS
Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition.


CONCLUSIONS
In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.
Gullick
Darren R
DR
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK. darren.gullick@port.ac.uk
Ingram
Matthew J
MJ
Pugh
W John
WJ
Cox
Paul A
PA
Gard
Paul
P
Smart
John D
JD
Moss
Gary P
GP
D000110:Acetylcholinesterase / Q000145:classification / Q000378:metabolism / Q000494:pharmacology; D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D002216:Captopril / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004722:Endoribonucleases / Q000378:metabolism / Q000494:pharmacology; D004950:Esterases / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006207:Half-Life; D020128:Inhibitory Concentration 50; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D012044:Regression Analysis; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine / Q000378:metabolism; D013997:Time Factors; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011355:Prodrugs; D000803:Angiotensin I; D002216:Captopril; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D004722:Endoribonucleases; D004950:Esterases; D000110:Acetylcholinesterase; C022537:ribonuclease E