Metabolism of CDRI-85/92, a new potent anti-ulcer agent, involving cis-trans conversion.
CDRI 85/92, an anti-ulcer drug, is a new proton pump inhibitor, currently in an advanced stage of drug development. To know more about the drug it was our objective to delineate/identify the metabolic pathway as well as the enzymes responsible for the formation of metabolites. Metabolism of CDRI-85/92 (cis-5-styryl-2-oxazolidinone-4-carboxylic acid) was investigated in rat liver cellular fractions (S9, microsomes and cytosol) using reverse-phase HPLC and mass spectrometry techniques. Two major metabolites were produced by rat liver S9 fractions and reducing factor generating system from either untreated rats or phenobarbitone (PB)-pretreated rats. Incubation of CDRI-85/92 with postmitochondrial fraction (S9) for 24 h resulted in a cis to trans conversion (metabolite M2). Further cis-trans metabolizing capacity was measured separately in the cytosolic and microsomal fractions. Incubation with the cytosolic fraction resulted in an increased rate of cis-trans conversion, while the microsomal fraction showed no cis to trans conversion, thereby restricting the cis to trans conversion to Phase II enzymes, which are mainly located in the cytosol. Studies with PB-pretreated rat liver S9 fractions resulted in an increased rate of cis to trans conversion. Another metabolite was also present (M1) which was identified as an oxygenated metabolite by mass spectrometry. The major urinary metabolite from CDRI-85/92-treated Sprague-Dawley rats (20 mg/kg p.o.) was identified as M2. Studies using sulfobromophthalein and N-ethylmaleimide, as specific inhibitors of GST, showed a complete absence of metabolism, thus indicating the involvement of GST in the metabolism of CDRI-85/92. This study will be helpful in providing clues about factors influencing the bioavailability of CDRI-85/92 as well as drug-drug interactions.
Srivastava
Pratima
P
Pharmacokinetics & Metabolism Division, Central Drug Research Institute, Lucknow, India.
Sharma
Preeti
P
Lal
Jawahar
J
Dikshit
Dinesh K
DK
Madhusudanan
Kunnath P
KP
Gupta
Ram C
RC
D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D000897:Anti-Ulcer Agents; C452083:CDRI-85-92; D010080:Oxazoles; D054328:Proton Pump Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D010634:Phenobarbital