Stereoselective hydroxylation of tacrine in rats and humans.
An enantiospecific method was developed for assessing the stereochemistry of tacrine (9-amino-1,2,3,4-tetrahydroacridine monohydrochloride monohydrate; THA) metabolism to 1-hydroxytacrine (1-OH-THA) in humans and rats. In addition, limited metabolic studies with human liver microsomal preparations were conducted, and the stereochemistry of rac-1-OH-THA disposition was also examined. The analytical method incorporates an achiral normal phase separation and isolation of 1-OH-THA, followed by a chromatographic step using chiral normal-phase chromatography to resolve the enantiomers of 1-OH-THA. The achiral method was applied to quantitation of total 1-OH-THA in human urine specimens collected for 24 hr following administration of a single 40 mg oral dose of tacrine to 15 healthy elderly volunteers. Total 1-OH-THA accounted for approximately 5% of the administered dose. THA and 2-OH-THA were also quantitated and found to comprise < 1% and approximately 2% of the administered dose, respectively. 4-OH-THA was not detectable. The dextrorotatory (+)-isomer comprised approximately 94% of the 1-OH-THA recovered in urine. In vitro studies utilizing human liver microsomes found enantioselective formation of the (+)-isomer (approximately 90%), whereas incubations with rac-1-OH-THA showed residual substrate to be racemic. The method was also applied to determination of the enantiomeric composition of 1-OH-THA in the urine of rats given a single oral 16 mg/kg dose of THA. The percentage of 1-OH-THA excreted in urine as the (+)-isomer was 94%.(ABSTRACT TRUNCATED AT 250 WORDS)
Hooper
W D
WD
Division of Clinical Pharmacology, University of Colorado School of Medicine.
Pool
W F
WF
Woolf
T F
TF
Gal
J
J
D000368:Aged; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D013237:Stereoisomerism; D013619:Tacrine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000652:urine
D002800:Cholinesterase Inhibitors; D005965:Glucuronates; D013619:Tacrine; C056424:velnacrine