Species differences in metabolism and pharmacokinetics of a sphingosine-1-phosphate receptor agonist in rats and dogs: formation of a unique glutathione adduct in the rat.
The pharmacokinetics and metabolism of 1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid (MRL-A), a selective agonist for the sphingosine-1-phosphate 1 (S1P1) receptor, were investigated in rats and dogs. In both species, more than 50% of the dose was excreted in bile. Specific to the rat, and observed in bile, were a taurine conjugate of MRL-A and a glucuronide conjugate of an azetidine lactam metabolite. In dogs, a smaller portion of the dose (54% of administered dose) was excreted intact in bile, and the major metabolites detected were an azetidine N-oxide of MRL-A and an acylglucuronide of an N-dealkylation product. This latter metabolite was also observed in rat bile. Stereoselective formation of the N-oxide isomer was observed in dogs, whereas the rat produced comparable amounts of both isomers. The formation of a unique glutathione adduct was observed in rat bile, which was proposed to occur via N-dealkylation, followed by reduction of the putative aldehyde product to form the alcohol, and dehydration of the alcohol to generate a reactive quinone methide intermediate. Incubation of a synthetic standard of this alcohol in rat microsomes fortified with reduced glutathione or rat hepatocytes resulted in formation of this unique glutathione adduct.
Anari
M Reza
MR
Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, P.O. Box 4, PA 19486, USA. reza_anari@yahoo.com
Creighton
Mellissa D
MD
Ngui
Jason S
JS
Tschirret-Guth
Richard A
RA
Teffera
Yohannes
Y
Doss
George A
GA
Tang
Wei
W
Yu
Nathan X
NX
Ciccotto
Suzanne L
SL
Hobra
Donald F
DF
Coleman
John B
JB
Vincent
Stella H
SH
Evans
David C
DC
D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism*; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D013045:Species Specificity; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine
C514353:1-(4-((4-phenyl-5-trifluoromethyl-2-thienyl)methoxy)benzyl)azetidine-3-carboxylic acid; D001384:Azetidines; D049349:Receptors, Lysosphingolipid; D013876:Thiophenes; D005978:Glutathione