In vitro metabolism of a new oxazolidinedione hypoglycemic agent utilizing liver microsomes and recombinant human cytochrome P450 enzymes.
The compound, 5-{4-[3-(4-cyclohexyl-2-propylphenoxy)propoxy]phenyl}-1,3-oxazolidine-2,4-dione (compound A) is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. PPARgamma agonists have proven useful in the treatment of type 2 diabetes, which is characterized by hyperglycemia, insulin resistance and/or abnormal insulin secretion. The metabolism of this oxazolidinedione (OZD) was investigated in male rat, dog, monkey and human liver microsomes, and recombinant human cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) in the presence of NADPH. Routes of metabolism included monohydroxylation of the cyclohexane ring at multiple positions, monohydroxylation of the n-propyl side chain or the tether linkage, and OZD ring opening, giving rise to the keto amide and alcohol amide entities. Liver microsomes showed subtle qualitative and quantitative metabolic differences among rat, dog, monkey and human preparations. Further, CYP2C8 and CYP2C19 did not display different regioselectivity for hydroxylation on the cyclohexane ring with both of them giving rise to C-3 and C-4 hydroxy metabolites, but they did display different stereoselectivity with CYP2C8 preferring cyclohexane hydroxylation in equatorial positions and CYP2C19 in axial positions.
Agrawal
Arun K
AK
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ, USA. arun.agrawal@pfizer.com
Hop
Cornelis E C A
CE
Pang
Jianmei
J
Silva Elipe
Maria V
MV
Desai
Ranjit C
RC
Leung
Kwan H
KH
Franklin
Ronald B
RB
D000818:Animals; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism*; D023303:Oxazolidinones / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism*
C502236:5-(4-(3-(4-cyclohexyl-2-propylphenoxy)propoxy)phenyl)-1,3-oxazolidine-2,4-dione; D007004:Hypoglycemic Agents; D010080:Oxazoles; D023303:Oxazolidinones; D047493:PPAR alpha; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System