DRUG METABOLISM

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DRUG METABOLISM: 

DRUG METABOLISM PATHWAYS OF DRUG METABOLISM INDUCERS & INHIBITORS OF DRUG METABOLISM SIGNIFICANCE OF DRUG METABOLISM IN MEDICINAL CHEMISTRY

Metabolism: It is body’s mechanism for processing , using, inactivating and eventually eliminating xenobiotics including drugs. Xenobiotics – foreign substances. Drug metabolism: It is the metabolism of drugs, their biochemical modification or degradation, usually through specialised enzymatic systems. Drug metabolism often converts lipophilic chemical compound into more readily excreted polar products. : 

Metabolism : It is body’s mechanism for processing , using, inactivating and eventually eliminating xenobiotics including drugs. Xenobiotics – foreign substances. Drug metabolism : It is the metabolism of drugs, their biochemical modification or degradation, usually through specialised enzymatic systems. Drug metabolism often converts lipophilic chemical compound into more readily excreted polar products.

Drug metabolism can result in toxification or detoxification – activation or deactivation of chemical while both can occur, the major metabolites of most drugs are detoxification products. So drug metabolism is a detoxification function the body possesses to defend itself from environment hostility and helps in drug elimination. Site of drug metabolism : Liver – Primary site, smooth endoplasmic reticulum of liver cell (hepatocyte). Contains necessary enzymes. : 

Drug metabolism can result in toxification or detoxification – activation or deactivation of chemical while both can occur, the major metabolites of most drugs are detoxification products. So drug metabolism is a detoxification function the body possesses to defend itself from environment hostility and helps in drug elimination. Site of drug metabolism : Liver – Primary site, smooth endoplasmic reticulum of liver cell (hepatocyte). Contains necessary enzymes.

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Metabolic process may increase or decrease the effects of drugs. Exs : Diazepam – 3-4 compounds ( more active than the original drug) Isoniazid - N-acetyl isoniazid (  effect) + CoASH . Other sites : GIT – epithelial cells of GIT and intestinal mucosa [(oral drugs) cytochrome P-450 - CYP3A4 isozyme ], Kidneys, lungs .

CYTOCHROME P-450 ENZYME: 

CYTOCHROME P-450 ENZYME The cytochromes are membrane bound proteins with an approximate mol.wt of 50 KD and contains a heme moiety. There are about 30 HUMAN cytochrome P-450 enzymes out of which 6-7 are the metabolising enzymes. They are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, CYP2A6. CYP2D6 nomenclature: CYP-cytochrome P450, 2= genetic family, D= genetic subfamily, 6= specific gene. This nomenclature is purely genetic and not functional based.

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The concentration of Cytochrome P-450 is high in the liver. 450nm -  max of complex formed by CYP with carbonmonoxide . Cytochrome P-450 monooxygenases are located in the endoplasmic reticulum present in liver cells which take part in oxidative biotransformations of xenobiotics .

R-H (DRUG )+NADPH +H + R-OH+NADP + +H 2 O During oxidative process, one atom of O 2 is inserted between substrate, often producing an unstable intermediate which breaks down to give the final product.

Factors affecting drug metabolism: 

Factors affecting drug metabolism Physicochemical properties of drugs : Molecular size, shape, acidity / basicity, lipophilicity , pKa , steric & electronic characteristics. Chemical factors : Insecticides, Carbonmonoxide and other drugs. Diet : Fat free diet will reduce CYP levels as phospholipids become deficient and this is an important component of microsome . Genetic/ hereditary factors : Different species have different population of enzymes which can cause difference in qualitative and quantitative differences in metabolism. Eg : Imipramine (antidepressant) acts only after desmethylation to desmethyl imipramine. This conversion is seen only in man and rats whereas in rabbits the 2-hydroxy derivative has been the major metabolite and little antidepressant like activity has been seen.

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Environmental factors : Concommittant drug therapy ( drugs taken for a long time might induce synthesis of drug metabolising enzymes which might metabolise the drug soon), smoking, alcohol etc. Physiologic factors : Age, sex, hormones, diseases and pregnancy. Coenzymes do not function properly at an early or young age and also at very old age. So drug action will be for long time . Sex also influences the drug metabolism as there are different conc. of enzymes found in male and females. Similarly liver diseases may change drug metabolism . Drugs like barbiturates and benzodiazepines pass from mother to fetus through placenta. Pharmacodynamic factors : Dose , frequency route of administration, tissue metabolism and protein binding might also influence drug metabolism.

Significance of Drug metabolism in medicinal chemistry: 

Significance of Drug metabolism in medicinal chemistry To select and monitor appropriate drug therapy for the patients. For successful determination of drug regimens (ADME). In diseased states the levels of metabolised drug ( active as well as inactive ) is important to know as the disease inhibits or expedites the xenobiotics metabolism. Metabolic data info. is important in preclinical and clinical testing and evaluation of new drugs for their safe and proper use.

GENERAL PATHWAYS OF DRUG METABOLISM: 

GENERAL PATHWAYS OF DRUG METABOLISM Metabolism conversions are classified as either phase –I and phase-II. These phase-I & phase-II reactions are biotransformations of chemicals. DRUG METABOLISM pathways: PHASE-I PHASE-II (Functional reactions) (Conjugation reactions)

Phase –I or Functionalisation reactions: 

Phase –I or Functionalisation reactions I-OXIDATION REACTIONS II-REDUCTION REACTIONS III-HYDROLYTIC REACTIONS

I-OXIDATION REACTIONS: 

I-OXIDATION REACTIONS Oxidation of aromatic moieties. Oxidation of olefins Oxidation of benzylic , allylic carbon atoms and C-atoms α - to carbonyl and imines. Oxidation at aliphatic and alicyclic carbon atoms. Oxidation involving carbon-heteroatom systems Carbon-nitrogen systems (aliphatic and aromatic). Carbon-oxygen systems . Carbon – sulphur systems. Oxidation of alcohols and aldehydes Other miscellaneous Oxidation reactions.

Reductive and hydrolytic reactions: 

Reductive and hydrolytic reactions II- Reductive reactions : Reduction of aldehydes and ketones. Reduction of nitro and azo compounds Miscellaneous reductive reactions. III- Hydrolytic reactions : Hydrolysis of esters and amides Hydrolysis of epoxides and arene oxides by epoxide hydrase .

Phase – I reactions:I-Oxidative reactions;: 

Phase – I reactions:I-Oxidative reactions; Oxidation of aromatic moieties : Aromatic hydroxylation takes place. Here oxidation of aromatic compounds ( arenes ) to their corresponding phenolic metabolites ( arenols )takes place. First an epoxide intermediate called an ‘ arene oxide’ is formed which rearranges rapidly and spontaneously to the arenol product in most instances.

Oxidation of Olefins:-C=C-: 

Oxidation of Olefins:-C=C- O OH OH -C=C- [O] -C - C- -C - C- Epoxides ( oxiranes ) from olefins are more stable than arene oxides. These epoxides are readily converted to 1,2-diols in the presence of the enzyme.

Oxidation at Benzylic C-atom:: 

Oxidation at Benzylic C-atom: Carbon attached to aromatic ring are susceptible to oxidation , thereby forming corresponding alcohols / carbinol metabolite. Primary alcohol metabolites are further oxidised to aldehydes and carboxylic acids . -C-H - C-OH [ CH 2 OH -CHO -COOH ]

Oxidation of Allylic C-atom:: 

Oxidation of Allylic C-atom: Microsomal hydroxylation at allylic C-atom is o bserved commonly in drug metabolism. The antiarrhythmic agent quinidine is metabolised by allylic hydroxylation to 3-hydroxy quinidine which shows significant antiarrythmic activity in animals and possibly in humans.

Oxidation at C-atoms  to carbonyl and Imines:: 

Oxidation at C-atoms  to carbonyl and Imines: Here mixed function oxidase system take part. Carbon adjacent to C=O & C=N are involved.

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In case of Diazepam ( Benzodiazepines) it is oxidised to its corresponding 3-hydroxy metabolite ( here hydroxylation is  to both ---- a lactam carbonyl as well an imino function )

Oxidation at aliphatic and alicyclic carbon atoms:: 

Oxidation at aliphatic and alicyclic carbon atoms: Alkyl/ aliphatic carbon centers are subjected to a mixed function oxidation. Metabolic oxidation at the terminal methyl group often is referred to as  (omega) oxidation and oxidation of penultimate carbon atom ( ie next to the last carbon atom) is called -1 oxidation. Metabolites from these oxidations are susceptible to further oxidation to yield aldehyde, ketones or carboxylic acids.

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Numerous barbiturates, oral hypoglycemics -- sulphonyl ureas , antiepileptics undergo  & -1 oxidation.

Oxidations involving carbon-heteroatom systems.: 

Oxidations involving carbon-heteroatom systems. N 2 and O 2 functionalities are commonly found in most of the drugs and foreign compounds. Sulfur functionalities occur occasionally. Metabolic oxidation of carbon-nitrogen, carbon –oxygen and carbon-sulfur systems involves two basic types of biotransformations . 1. Hydroxylation of -carbon atom attached directly to the heteroatom (N, O, S). Oxidative N, O & S dealkylation as well as oxidative deamination reactions fall under this mechanistic pathway.

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2. Hydroxylation / Oxidation of the heteroatom ( N, S only eg : N-hydroxylation, N-oxide formation, sulfoxide and sulfone formation ) Oxidation involving carbon-nitrogen systems ; Amines , amides are present in natural products like morphine, cocaine, nicotine and drugs like phenothiazines , antihistamines, tricyclic antidepressants, -adrenergic agents, benzodiazepines. Either -class hydroxylation or N-oxidation takes place with the help of cytochrome P-450 mixed function oxidases and amine oxidases (N-oxidases).

Tertiary and aliphatic amines: 

Tertiary and aliphatic amines This drug here undergoes oxidative N- dealkylation . Alicyclic tertiary amine like Nicotine undergoes -carbon hydroxylation.

Secondary and Primary amines: Oxidative N-dealkylation, deamination and N-oxidation reactions :: 

Secondary and Primary amines: Oxidative N- dealkylation , deamination and N-oxidation reactions :

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N-oxidation of secondary aliphatic & alicyclic amines leads to several N-oxygenated products :

Thanks Amit Gupta And Priya Mishra: 

Thanks Amit Gupta And Priya Mishra Dr.H.S.Gour university sagar m.p ,India