Drug biotransformationn

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Drug biotransformationn

  1. 1. DRUG-BIOTRANSFORMATION FEB 2014 DRUG-BIOTRANSFORMATION It is the chemical alteration of the drug within the body, site of metabolism: liver, kidney, intestine, Plasma, Lung. Importance / Consequences of Biotransformation (1) Activation of Pro-drug: Enalapril → Enalaprilat Dipivefrine→ Epinephrine Bacampicillin→ Ampicillin Levodopa→Dopamine (2) Allows convertion of lipophilic drug to more ionized form & polar form. ↓ Cannot be reabsorbed Therefore facilitate excretion by kidney (Termination of action of a drug) (3) Parent drugs can be converted to less pharmacologically active metabolite (↓ Action). (4) Biotransformation can lead to formation of active metabolite as well as more toxic products than the parent molecule. e.g Diazepam→Desmethyl Diazepam Codeine → Morphine PCM → NAPBQI Amitriptyline →Nortriptiline Biotransformation The processes of biotransformation can be broadly classified as: Phase I reaction (pre-synthetic reaction) Phase II reaction (Synthetic reaction) Phase I reaction Parent drugs are converted to more polar compounds by introducing or unmasking chemical groups such as - OH - NH2 - SH gp - Reaction involved: Oxidation Reduction Hydrolysis 1
  2. 2. DRUG-BIOTRANSFORMATION - FEB 2014 Cyclization Decyclization The metabolite of this reaction can be  active  Inactive Note: When the metabolites are polar enough, they can get excreted readily in urine. However, in most cases, the phase I metabolites have to undergo some more ( Phase II) reaction to get eliminated. Oxidation Chemically defined as (i) Addition of oxygen (ii) Removal of Hydrogen (iii) Increase in oxidation state Microsomal drug oxidation are carried out by an important group of enzyme known as mixed function oxidase (abundant in microsome of liver). The final step of the reaction uses NADPH as reducing agent, Molecular oxygen and Cytochrome P450 reductase. N.B: CYP 450→ Sluggish catalyst;Therefore reaction is very slow. e.g De-alkylation oxidation CH3 R H N R N CH3 CH3 e.g Drugs undergoing oxidation: Diazepam/ Barbiturates/ Phenytoin/ Theophylline Alcohol/ Adrenaline Hydrolysis  Involves addition of water molecule to a drug molecule.  Esters (enzyme involved: Esterase) / Amides ( Amidase) and Polypeptides (Peptidase) undergo hydrolysis. The process usually occurs in the liver, intestine or Plasma. Examples of drugs undergoing Hydrolysis Procainamide /Procaine/ Lignocaine / Oxytocin/Choline esterase 2
  3. 3. DRUG-BIOTRANSFORMATION FEB 2014 Cyclization Formation of a ring structure from a straight chain compound e.g proguanil. Decyclization Minor pathway  Involves opening of a cyclic structure. Example: Phenytoin / Barbiturates. Phase II reaction (Synthetic Reaction)  Relatively faster than Phase I REACTION.  The metabolites form are mostly inactive and highly ionized that can be excreted readily  In general, they occur after Phase I reaction. However, they can also occur first Example Isoniazid (Phase II) →N-acetyl conjugate ↓ hydrolysis (Phase I) Isonicotinic acid excreted Usually Phase II reaction involve conjugate of a drug or its phase I metabolite to form polar compound tha is easily excreted. Phase II reaction (1) Glucoronide conjugation (2) Acetylation (3) Methylation (4) Sulfate conjugate (5) Glycine conjugation (6) Glutathione conjugation (7) Ribonucleotide/nucleoside synthesis. Conjugation reactions are highly energy dependent. 3
  4. 4. DRUG-BIOTRANSFORMATION FEB 2014 Glucoronide conjugation  Importance phase II reaction  Compounds with hydroxyl and carboxy gp are easily conjugated with UDP glucoronic acid, (derived from glucose in the presence of glucoronyl transferase). e.g Morphine Diclofenac PCM Digoxin Sulfonamides Endogeneous substance e.g Thyroxine / Bilirubin / Steroidal hormone N.B: Drug glucoronide that are excreted in bile can be hydrolysed by β-glucoronidase and undergoes enterohepatic recycling ↓ Prolonging duration of activation of such drugs e.g oral contraceptives. Acetylation  Substance having Amine/ hydrazine/ residues undergoes acetylation.  Example: Sulfonamides/ hydralazine/ Isoniazid/ Dapsone /PAS/ Clonazepam.  Conjugated with Acetyl COA in presence of N-acetyl transferase  Acetylator status shows genetic polymorphism: Slow acetylators are prone to neurotoxicity and fast acetylators are proned to hepatotoxicity. Glutathione conjugation  Minor pathway of biotransformation  Drugs containing the following groups are likely to undergo glutathione conjugation: Epoxides, Hydroxylamine, Cpds containing nitro gp, Oxides. e.g PCM, Ethacrylic acid / Bromobenzene When large amount of such intermediated are formed GSH become deficient ↓ Toxic adducts are formed ↓ Tissue damage Glycine conjugation: (minor pathway) Drugs that are Acetyl COA derivatives of carboxylic Acid such as ( Salicylates /Nicotinic Acid /Benzoic Acid) gets conjugated with glycine In the presence of Acetyl COA transferase. 4
  5. 5. DRUG-BIOTRANSFORMATION FEB 2014 Sulphate Conjugation Phenol/ Alcohol/ Aromatic Cpd such as estrone , Paracetamol, Methyldopa, Coumarins undergoes conjugation with phospho-adenosyl phosphosulphate in the presence of sulphotransferase. Methylation Drugs containing catecholamines, Amine and phenol groups like (Adrenaline /Dopamine/Histamine/Thioroucil) gets methylated with S-aderosyl methionine or cysteine in presence of transmethylase. Ribonucleoside/ Nucleotide synthesis They are important biotransformation reaction for inactivation of many purine/ Pyramidine anti-metabolites especially cancer chemotherapy agents. Microsomal enzyme  Located on smooth endoplastic Reticulum.  Primarily in liver /Kidney / intestinal mucosa & lungs e.g CyP450/ Mono-oxygenase /Glucoronyl transferase They catalyse oxidation, Reduction, hydrolysis and Glucoronidation. NON-Microsomal enzyme Present in cytoplasm /mitochondria of hepatic cells & other tissues as well as plasma e.g Oxidases /Esterases/ Amidases. They catalyse: Oxidation /Reduction/ All conjugation except glucoronidation. Hoffmann elimination Refers to inactivation of drugs in body fluid by spontaneous molecular rearrangement without the need for enzymes. e.g Atracurium. References: th 1. BERTRAM,G.K., SUSAN,B. & ANTHONY, J.T.,2010. Basic and clinical pharmacology. 12 ed. US: Mc Graw Hill. th 2. GOODMAN & GILMAN’S.,2011. The pharmacological basis of therapeutics. 12 ed. US: Mc Graw Hill. 5
  6. 6. DRUG-BIOTRANSFORMATION FEB 2014 6

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