In vitro and in vivo biotransformations of the naphthalenic lignan lactone 5-lipoxygenase inhibitor, L-702,539.
It has been reported previously that the tetrahydropyranyl naphthtalenic lignan lactone L-702,539 is a potent nonredox, 5-lipoxygenase inhibitor that has the advantage that it can be dosed either as the lactone or as the corresponding nonactive hydroxy acid L-702,618 (opened lactone). Studies with hepatic microsomes from the rat, rhesus monkey, and human were undertaken in a phosphate buffer and suggested that the closure of the hydroxy acid L-702,618 to the lactone L-702,539 was an enzymatic process. The incubation of L-702,539 under oxidative conditions with these specific hepatic microsomes resulted in the formation of three significant metabolites (> 0.4 nmol/mg protein/hr) as determined by HPLC with UV detection. These metabolites were isolated from large microsomal incubations and were characterized by MS and NMR spectroscopy. Data showed that the lactone and tetrahydropyran portions of the molecule were both susceptible to hydroxylation, and the hydroxylated tetrahydropyran was further oxidized to the hydroxy acid. Analysis of plasma samples obtained from rat and rhesus monkeys following L-702,618 administration indicated that the in vivo metabolic pathway was similar to the one observed in vitro using hepatic microsomes. Studies conducted with microsomes from genetically engineered human cell lines expressing individual cytochrome P450s indicated that the isozyme responsible for the metabolism at the tetrahydropyran ring, was P4503A4. These findings were supported by studies conducted in human microsomes using an inhibitory P4503A4 antibody and troleandomycin, which is a potent P4503A inhibitor.
Chauret
N
N
Medicinal Chemistry Department, Merck Frosst Centre for Therapeutic Research, Quebec, Canada.
Li
C
C
Ducharme
Y
Y
Trimble
L A
LA
Yergey
J A
JA
Ramachandran
C
C
Nicoll-Griffith
D A
DA
D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics*; D001711:Biotransformation; D015153:Blotting, Western; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics*; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D001572:Benzofurans; C093188:L 702539; D016859:Lipoxygenase Inhibitors; D003577:Cytochrome P-450 Enzyme System