Stereoselective metabolism of a new anticonvulsant drug candidate, losigamone, by human liver microsomes.
Losigamone (LSG) is a new candidate anticonvulsant drug under going preclinical and clinical development. Metabolism of racemic (+/-)-LSG and its two enantiomers, AO-242 [(+)-LSG] and AO-294 [(-)-LSG], was studied using human liver microsomes and recombinant cytochrome P450 isozymes. HPLC with both UV and electrochemical detection was used for analysis of the incubation media. Five metabolites (M1, M2, M3, M4, and M5) were generated from racemic (+/-)-LSG by both human liver microsomes and recombinant enzymes. Stereoselective metabolism was observed when each enantiomer was incubated separately with human liver microsomes. M1 was the major metabolite produced from (+)-LSG, whereas M3, M4, and M5 were primarily produced from (-)-LSG. The production of M1 from (+)-LSG was markedly inhibited by (-)-LSG, indicating a metabolic enantiomer/enantiomer interaction. (+/-)-LSG enantiomers were selectively metabolized by recombinant cytochrome P450 2A6, and the metabolism of (+)-LSG and (-)-LSG by human liver microsomes was preferentially inhibited by coumarin, a cytochrome P450 2A6-selective compound.
Torchin
C D
CD
Epilepsy Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
McNeilly
P J
PJ
Kapetanovic
I M
IM
Strong
J M
JM
Kupferberg
H J
HJ
D000927:Anticonvulsants / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000494:pharmacology; D065637:Cytochrome P-450 CYP2A6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005663:Furans / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D000077213:Lamotrigine; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D014227:Triazines / Q000494:pharmacology
D000927:Anticonvulsants; D003374:Coumarins; D065607:Cytochrome P-450 Enzyme Inhibitors; D005663:Furans; D007527:Isoenzymes; D011994:Recombinant Proteins; D014227:Triazines; D010672:Phenytoin; C065427:losigame; D003577:Cytochrome P-450 Enzyme System; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D000077213:Lamotrigine