Metabolism of catecholamine esters by cultured bovine brain microvessel endothelial cells.
The metabolism of epinine (N-methyldopamine) and epinine diesters (acetyl, benzoyl, pivaloyl, and isobutyryl) by brain endothelium was investigated using primary cultures of bovine brain microvessel endothelial cells. 3,4-Dihydroxyphenylacetic acid (DOPAC), the product of monoamine oxidase (MAO)-mediated degradation of epinine, was the only metabolite detected by HPLC with electrochemical detection following incubation of the cell monolayers with epinine or its esters. This metabolism could be inhibited by the MAO inhibitors pargyline, clorgyline, and deprenyl, with the system being most sensitive to inhibition by clorgyline. Compared with epinine, incubation of cell monolayers with the diester prodrugs led to increased drug (epinine plus epinine diesters) tissue levels. With the exception of the diacetyl ester, lower levels of DOPAC were observed with the diester prodrugs than with the parent compound. Hydrolysis by serine-dependent esterases appears to be necessary for the subsequent oxidation by MAO. The permeabilities of epinine and the diester prodrugs through endothelial cell monolayers grown on porous supports were related to their lipophilicity and molecular weight.
Scriba
G K
GK
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence 66045.
Borchardt
R T
RT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003846:Deoxyepinephrine / Q000031:analogs & derivatives / Q000378:metabolism*; D004298:Dopamine / Q000031:analogs & derivatives*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D007531:Isoflurophate / Q000494:pharmacology; D008750:Methyldopa / Q000031:analogs & derivatives / Q000378:metabolism; D008833:Microcirculation; D010293:Pargyline / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism; D014665:Vasodilator Agents
D011355:Prodrugs; D014665:Vasodilator Agents; D015102:3,4-Dihydroxyphenylacetic Acid; D007531:Isoflurophate; D008750:Methyldopa; C037908:methyldopa pivaloyloxyethyl ester; C023487:ibopamine; D010293:Pargyline; D003846:Deoxyepinephrine; D004298:Dopamine