Oxidation of aldose reductase inhibitors ALO-4114 and ALO-3152 catalyzed by liver microsomes.
Rat and Cynomolgus monkey liver microsomes catalyze the oxidation of 2.7-difluoro-4.5-dimethoxyspiro (9H-fluorene-9,4'-imidazolidine)-2',5'-dione (ALO-4114) to its monomethoxymetabolite (ALO-4417). Formation of this product by O-demethylation of ALO-4114 is catalyzed by NADPH and oxygen-dependent microsomal enzymes with the properties of P-450 monooxygenases. The reaction is blocked by inhibitors selective for these enzymes and activity increases about 2-fold in rats pretreated with phenobarbital or methylcholanthrene. The increase in the O-demethylation of ALO-4114 was, however, considerably less than the increase in benzphetamine N-demethylation or nitrophenetole O-deethylation activities in liver microsomes from rats pretreated with either phenobarbital or methylcholanthrene. Rats pretreated with 20 or 40 mg/kg of ALO-4114 for 3-4 days failed to change significantly the rate of ALO-4114 O-demethylase activity of liver microsomes. O-Demethylation of the achiral ALO-4114 yields the chiral ALO-4417. The enantiomers separated on a Daicel Chiracel AS column by HPLC indicated that O-demethylation of ALO-4114 by microsomes from untreated rats was only slightly stereoselective. However, rats pretreated with methylcholanthrene not only enhanced activity, but also increased the formation of one enantiomer. Further oxidative metabolism of the enantiomers was slow and barely detectable in vitro. Studies conducted with Cynomolgus monkey liver microsomes from one male and one female per experimental group were generally consistent with those from the rat, but some differences were noted. Whether the differences are real or only reflect individual variations caused by the small sample size is not known at present.
Department of Chemistry and Biochemistry, University of Texas, Austin 78712.
A D
AD
Kiss
K
K
Haggard
J C
JC
Veltman
D M
DM
Ziegler
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003640:Dealkylation; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics*; D006827:Hydantoins / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000493:pharmacokinetics*; D013237:Stereoisomerism
D005449:Fluorenes; D006827:Hydantoins; D013141:Spiro Compounds; C076003:AL 3152; C079554:AL 4114; D000449:Aldehyde Reductase