Essay: Metabolites formed in vivo

1: Systemic levels of the chemical entities can be observed within 2 to 3 hours. Compound A ethyl pyrazole ring attached to oxo pyramidine ring attached to benzyl solfoxo piperazine. Compound B has dioxypiparazine ring and a dioxybenze and a indole.
The major p450 metabolism for both the compounds will be demythylation. Compound A can undergo hydroxylation to aliphatic side chain. Piperazine may undergo oxidation and demethylation of pyrazole. Compound B can undergo demethylation of piperazine and hydroxylation as major metabolites.
2. Hydroxy acetyl amino flourene is the major and initial metabolite formed from 2 aminoflourene by phase 1 enzymes. Hydroxyl acetyl amino flourene can be glucouronidate by glucouronyltransferase to inactive metabolite. Futher metabolism of hydroxyl acetylaminoflourene is carried out by phase 2 enzymes such as sulfonyl tranferase and n acetyl tranferase for ming respective metabolite such as sulfoactylaminoflourene and hydroxyl acetyl nitrinium ion which is further converted to carbonium ion which inturn form DNA adducts. 2 amino flourene is metabolized initially through cyp450 enzymes to hydroxyacetylamino flourene which is further converted to either hydroxyl sufoacetylaminoflourene by sulfotransferase or actylated by N actyl tranferase leading to nitrinium ion and DNA adducts these are inducible enzymes and prone to geneteci polymorphism Initial metabolism of 2 aminoflourene is by phase one CYP enzymes whereas further reactions are carried out phase 2 enzymes
3. My first study as a drug metabolism scientist for understanding a new chemical entity would be an in vitro incubation of the NCE with Liver S9 and analyzing for drug stability and metabolite profile. Liver S9 contains both cytosolic fraction as well as microsomal fraction to cover broader enzymes that possibly metabolize the NCE. It is important to conduct this experiment because it gives us better idea of possible metabolites formed in vivo at a lesser cost and we can assess the toxicity profile and species differences of the compound before further development if we use S9 from different species. I would use a concentration around Km for these studies. The second experiment I would do is the enzyme inhibition study using various enzymes such as CYP3A4, CYP 2D6 etc. to understand the effect of drug on the enzyme activity as altering the enzyme activity leads to severe drug interactions and thereby toxicity. I would do in detail inhibitor and induction studies of the NCE during the process of development before the NDA.4. Reactive metabolites are formed by various mechanisms catalyzed by many enzyme systems. The major pathways of xenobiotic metabolism involved are oxidation, reduction, hydrolysis, elimination and substitution. Flavin mono oxidases oxidize nitrogen, sulfur and organo phosphorous containing compounds. Alcohol and aldehyde dehydrogenases are involved in oxidation of aldehydes and alcohols respectively. Monoamine oxidases are involved in oxidation of alkyl halides and conversion of amines into imines. 2 Amino flourene metabolism is a good example for formation of electrophilic toxic metabolites which form DNA adducts.

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