Metabolism

MetabolismTerodiline Aromatic p-hydroxylation predominate with R but benzylic hydroxylation is preferred with S (homework)ReductionPlay an important role in the metabolism of compounds containing azo, nitro, and carbonylReductionA- Reduction of aldehyde and ketonesB- Reduction of nitro and azo compounds C- Reduction of sulfonesAzo reduction

Nitro reduction

Aldehyde and ketones (CO)

Reduction of sulfone

N.B sometimes Sulphur metabolized to O

Hydrolytic reactionsA-Esters hydrolysis B- Amide hydrolysisOne of the major biotransformation reactionsCarried out by non specific esterases found in kidney, liver and intestine (and pseudo choline esterase in plasma)Amides undergo hydrolysis by liver microsomal amidases, and esterases.Amides hydrolyzed more slowly than esters.

I-Ester hydrolysis

2-Amide hydrolysis

Effect of metabolism on therapeutic activityImipramine----desipramine (more antidepressant)Iproniazid (antidepressant)--------- INH (anti T.B)Phase II reactionsGlucuronide conjugationSulphate conjugationAcetylation and acylationGlycine conjugationGlutathion( not all in the liver)Glucuronide conjugation

Liver enzyme catalyze synthesis of uridene diphosphate glucoronic acid (UDPGA)It affect OH,SH,COOH,CONHXenobiotic reacts with the activated form of glucuronic acid (UDPGA) to form highly water soluble conjugate. This reaction is catalysed by microsomal uridine diphosphate glucuranyl transferase(UDPG-transferase).

Sulphate conjugationFor phenols, alcohols and amines.It originates from the body sulfate pole. Activated by conjugation with ATP to form 3-phosphoadenosine-5-phosphosulfate(PAPS)Then the sulfate moiety of PAPS bind to OH----------under the effect of sulphotransferase

Acylation reactionsOccur with NH2,OH and SH

Although water solubility is not increased ,it helps in terminating the pharmacological activity of the drug or its amino metabolite.Acetyl transferase is found in many tissues e.g liverAmino acid conjugationAmino acid glycine and glutamine are most common.For COOH and aromatic acids Amino acids are not converted to activated enzymes but COOH is activated with ATP and CoAto form acyl CoA which acylate A.A

Glutathione and mercaptouric acid conjugationGSH is a thiol containing tripeptideIt plays an important role in detoxification(for electrophilic compounds).(caused by the presence of electron with drowing groups as X,NO2,NO3,epoxide)It protect vital constituents by its nucleophilic SH gp.Conjugation is catalyzed by glutathione S-transferase.Degradation of GSH conjugates ----to mercaptouric acid by microsomal enzymes