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Information about Biotransformation

Published on March 4, 2014

Author: mbbaraker


Biotransformation of drugs: Biotransformation of drugs by Hardik shah Introduction: Introduction Biotransformation of drugs is defined as the conversion from one chemical form to another . Definition excludes the chemical instability of a drug. It is kind of an metabolic system which transform the water insoluble, lipophilic , non-polar drugs into polar and water-soluble products that can be easily excreted by the kidneys and are poorly reabsorbed; for instance, hippuric acid, the metabolite of benzoic acid, is 2.5 times more soluble. All chemical substances that are not nutrients for the body and enter the body through ingestion, inhalation or absorption are called as xenobiotics . Drug biotransformation is thus a detoxification process. Biotransformation: Biotransformation It normally results in Pharmacologic inactivation . E.g Phenobarbital to Hydroxyphenobarbital . It occasionaly yields metabolites with equal activity. E.g Imipramine to Desipramine . It rarely leads to toxicologic activation of drugs. E.g isoniazid forms tissue acylating intermediate. Some drugs undergo pharmacologic activation . E.g Aspirin to salicylic acid . Drug metabolizing organs : Drug metabolizing organs Liver is the primary site for metabolism of almost all drugs. Metabolism of organs other than liver is called as Extrahepatic metabolism and is of minor importance. Various organs in decreasing order of their metabolizing ability is; Liver > Lungs > Kidneys > intestine > placenta > adrenals > skin. Drug metabolizing enzymes: Drug metabolizing enzymes Broadly of two types Microsomal Non- microsomal The microsomal enzymes catalyze a majority of drug biotransformation reactions which includes a number of oxidative, reductive, hydrolytic and glucuronidation reactions. Characteristics of microsomal enzymes: Characteristics of microsomal enzymes The intact nature of lipoidal membrane bound enzyme of the microsomes is essential for its selectivity towards lipid-soluble substrates. A number of lipid-soluble substrates can interact nonspecifically with the microsomal enzymes. The lipid soluble substrate is biotransformed into a water-soluble metabolite by the microsomal enzymes which can be readily excreted. Nonmicrosomal enzymes: Nonmicrosomal enzymes It includes those enzymes that are present in soluble form in the cytoplasm and those attached to the mitochondria. These are non-specific enzymes that catalyze few oxidative, number of reductive and hydrolytic reactions and conjugation reactions. Nonmicrosomal enzymes act on relatively water-soluble endogenous enzymes. E.g oxidases , peroxidases , dehydrogenases , esterase. PowerPoint Presentation: Drug Metabolism Hepatic microsomal enzymes (oxidation, conjugation) Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic non- microsomal enzymes ( acetylation , sulfation,GSH , alcohol/ aldehyde dehydrogenase , hydrolysis, ox/red) Chemical pathways of drug biotransformation: Chemical pathways of drug biotransformation Phase 1 reactions : It includes oxidative, reductive and hydrolytic reactions. In these reactions a polar functional group is either introduces or unmasked if already present on the otherwise lipid soluble substrate e.g. –OH, -COOH, -NH 2 and –SH. Thus phase 1 reactions are also called as functionalization reactions. These transformation are also called as asynthetic reactions. Phase 2 reactions: Phase 2 reactions These reactions involve covalent attachment of small polar endogenous molecules such as glucuronic acid, sulfate, glycine etc to either unchanged drug or phase 1 products having suitable functional group to form highly water-soluble conjugates which are readily excreted by the kidneys or bile. Thus these reactions are also called as conjugation reactions . Also called as synthetic reactions . Phase 2 reactions are better known as true detoxification reactions . The enzymes responsible are called as transferases . Phase 1 reactions: Phase 1 reactions Oxidative reactions Most important and most common, almost all drugs that undergo phase 1 biotransformation undergo oxidation at some stage or other. It increases hydrophilicity of xenobiotics by introducing polar functional groups such –OH. PowerPoint Presentation: Examples: acetanilide, phenytoin , propranolol Endogenous substrates: steroid hormones (not aromatic amino acid s) Aromatic Hydroxylation R unstable arene epoxide intermediate non- enzymatic HYL1 epoxide hydrolase R OH OH R OH O DNA, Protein toxic reactions O R R OH R OH or Catechol Arenol Oxidation of aliphatic carbon atoms (Aliphatic Hydroxylation) :  Oxidation of aliphatic carbon atoms (Aliphatic Hydroxylation) Oxidation of Carbon-Heteroatom systems (Dealkylation): Oxidation of Carbon-Heteroatom systems ( Dealkylation ) Dealkylations include N-, O- and S- dealkylation . R-X-CH 2 -R’ [R-X-CH(OH)-R’] R-XH + O=CH-R’ [O ] X = O, N, S N-Dealkylation: N- Dealkylation Dealkylation of secondary or tertiary amines will produce primary amines and aldehydes . O-Dealkylation: O- Dealkylation Dealkylation of ethers or esters will produce phenols and aldehydes . Codeine Morphine S-Dealkylation: S- Dealkylation S- dealkylation usually produces sulfhydryl group and aldehyde . R-S-CH 3 [R-S-CH 2 OH] R-SH + HCHO 6-methylthiopurine 6-thiopurine [O] Hydroxylated intermediate Deamination: Deamination Deamination may produce ketone and ammonia. For example, deamination of amphetamine: Carbinolamine S-oxidation:  S-oxidation For example, S-oxidation of chlorpromazine: Sulfones N-oxidation:  N-oxidation For example, N-oxidation of chlorpheniramine PowerPoint Presentation: Other oxidases Monoamine oxidase These enzymes exist in mitochondria . They catalyze oxidation of amines into aldehyde and ammonia. For example, degradation of 5-hydroxytryptamine. RCH 2 -NH 2 RCH=NH RCHO + NH 3 [O] H 2 O PowerPoint Presentation: Alcohol and aldehyde oxidases R-CHOH R-CHO R-COOH Alcohol dehydrogenase Aldehyde dehydrogenase Reductions: Reductions Aldo- keto - reductases : these enzymes catalyze reduction of ketones or aldehydes to alcohols . Reaction is catalyzed by ninmicrosomal enzymes. For example: CCl 3 CHO CCl 3 CH 2 OH The coenzyme may be NADH or NADPH. 2H Trichloroacetaldehyde Trichloroethanol PowerPoint Presentation: Reductases for Azo or nitro compounds These reductases mainly exist in hepatic mitochondria with NADH or NADPH as coenzyme . Azo Nitrobenzene Amine Nitrosobenzene Hydrazo Hydroxylbenzamine Aniline Hydrolysis:  Hydrolysis Esters and amides are hydrolyzed to produce acids and alcohol or amine . Reaction are catalyzed by esterases . Ester(Procain) Para-aminobenzoic acid PowerPoint Presentation: Hydrolysis of amides Reactions are catalyzed by amidases . R-CO-NHR’ R-CO-OH + R’NH 2 E.g : Procainamide gets converted to PABA Phase 2 reactions: Phase 2 reactions These reactions include glucuronidation , sulfation , acetylation , methylation and amino acid binding. The moieties transferred to the substrates in a phase 2 reaction possess 3 characteristics They are simple endogenous molecules. They are of large molecular size. They are strongly polar or ionic in nature in order to render the substrate water-soluble. Glucuronidation: Glucuronidation Sulfation PAPS is the phosphate donor.: Sulfation PAPS is the phosphate donor. ( PAPS, 3’-phosphoadenosine- 5’-phosphosulfate) Sulfotransferase Acetylation: Acetylation Acetylation may reduce the water solubility of the compounds. Methylation: Methylation Methylation of phenols, amines and biologically active molecules may change their activity or toxicity. Generally, methylation reduces the hydrophilicity of the compound. S- adenosylmethionine (SAM) is the donor of methyl group. Methylation includes N- or O- methylation . PowerPoint Presentation: Methylation RH R-CH 3 SAM Factors affecting biotransformation of drugs: Factors affecting biotransformation of drugs Physicochemical properties of drug Molecular size and shape, pKa , acidity/ basicity , lipophilicity and steric and electronic characteristics. Chemical factors Induction of drug metabolizing enzymes Inhibition of drug metabolizing enzymes Environmental chemicals Biological factors : Species differences, strain differences, sex, age, diet, altered physiologic factors (pregnancy, hormonal imbalance, disease states) and temporal factors ( circadian rhythm ) Chemical factors: Chemical factors Induction of drug metabolizing enzymes The phenomenon of increased drug metabolizing ability of the enzymes by several drugs and chemicals is called as enzyme induction and the agents which bring about such an effect are known as inducers. Two types: Phenobarbital type inducers Polycyclic hydrocarbon type inducers Some drugs such as carbamazepine , cyclophosphamide , rifampicin etc stimulate their own metabolism, the phenomenon is known as auto-induction or self-induction. PowerPoint Presentation: Inhibition of drug metabolizing enzymes A decrease in the drug metabolizing ability of an enzyme is called as enzyme inhibition. Two types Direct inhibition Competitive inhibition: e.g methacholine inhibits metabolism of acetyl choline by competing with it for cholinesterase. Noncompetitive inhibition: e.g Isoniazid inhibits the metabolism of phenytoin . Indirect inhibition Repression Altered physiology. PowerPoint Presentation: Thank You

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