High-performance liquid chromatography study of stereospecific microsomal enzymes catalysing the reduction of a potential cytostatic drug, oracin. Interspecies comparison.
One of the main metabolites of oracin (I) ¿6-[2-(2-hydroxyethyl)aminoethyl]-5,11-dioxo-5,6-dihydro-11H-indeno[1,2- c] isoquinoline¿, a potential cytostatic drug, is 11-dihydrooracin (II) ¿(+),(-)-6-[2-(2-hydroxyethyl)aminoethyl]-5-oxo-11-hydroxy-5,6-dihydro-1 1H- indeno[1,2-c]isoquinoline¿, a metabolite formed by the reduction of oracin's pro-chiral centre on C 11. This metabolite has been found in all laboratory species in vitro and in vivo and it constitutes the main metabolite in man. The stereospecificity of reducing enzymes participating in the oracin biotransformation pathway was investigated using microsomal preparations from standard laboratory animals. Enzyme stereospecificity has been defined as preferential formation by the enzyme of the (+) or (-) stereoisomer of II. Significant interspecies differences were observed in the stereospecificity of the respective biotransformation enzymes. HPLC quantitative determinations of both enantiomers were performed using a Chiralcel OD-R column as chiral stationary phase with excellent resolution and stability.
Wsól
V
V
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic.
Szotáková
B
B
Kvasnicková
E
E
Fell
A F
AF
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004983:Ethanolamines / Q000737:chemistry / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000201:enzymology*; D008968:Molecular Conformation; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013552:Swine
D000970:Antineoplastic Agents; D004983:Ethanolamines; D007546:Isoquinolines; C103439:oracine