Principles of Drug Biotransfornation

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DRUG METABOLISM• What is Metabolism?• Drug metabolism specific organs • Role/purpose of drug biotransformation • Principles of drug biotransformationBiotransformation a series of enzyme-catalyzed processes—that alters the physiochemical properties of foreign chemicals (drug/xenobiotics) from those that favor absorption across biological membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )Drug Metabolism (Biotransformation)• Humans/Animals exposure

Transcript of Principles of Drug Biotransfornation


What is Metabolism? Drug metabolism specific organs Role/purpose of drug biotransformation Principles of drug biotransformation

Biotransformation a series of enzyme-catalyzed processesthat alters the physiochemical properties of foreign chemicals (drug/xenobiotics) from those that favor absorption across biological membranes (lipophilicity) to those favoring elimination in urine or bile (hydrophilicity )

Drug Metabolism (Biotransformation) Humans/Animals exposure: throgh air, water and food xenobiotics, including Drugs Metabolism/ Biotransformation / Detoxification . The process describes attenuation or loss of pharmacological activity of a drug/xenobiotic , due to enzymatically controlled chemical activity or toxicity of the resulting metabolite Metabolized in the body mainly to inactive substances Metabolism makes the compound less lipid soluble and more polar and thus hydrophilic.


Significance of drug metabolism Drugs are mostly lipid soluble, easy to cross membranes, bind to plasma proteins & reabsorb from renal tubules Metabolism changes them to water soluble & easily excretable products; also become inactive or less active Sometimes, a drug when taken is inactive (Pro-drugs) and is metabolizing to active compound in the body Occasionally, drugs may be changed to toxic compounds important in therapy in Age Group/ Organ Dysfunction therapeutic index, adverse drug effects/ toxicity pregnancy status/ neonates s5

Site/Organs of drug metabolismThe major site of drug metabolism is the liver (microsomal enzyme systems of hepatocytes) Secondary organs of biotransformation kidney (proximal tubule) lungs (type II cells) testes (Sertoli cells) skin (epithelial cells); plasma. nervous tissue (brain); intestines

Factors Affecting Drug Metabolism 1. Species differences : eg in phenylbutazone, procaine and barbiturates. 2. Genetic differences variation exist with species 3. Age of animal feeble in fetus,aged, newborn. under the influence of sex hormones. 5. Nutrition: starvation and malnutrition 6. Patholigical conditions: Liver/Kidney dysfunction

Xenobiotic PHASE I Expose or Add Biosynthetic functional groups conjugationOxidation Reduction Hydrolysis

Primary products PHASE II : biosynthetic conjugation Secondary products Elimination/excretions

TYPES OF BIOTRANSFORMATIONTwo phases in the metabolism of drugs:Phase 1 reaction. (Non synthetic phase). a change in drug molecule. oxidation, reduction or hydrolysis. result in activation, change or inactivation of drug. Phase II reaction. (Synthetic phase) Last step in detoxification reactions and almost always results in loss of biological activity of a compound. May be preceded by one or more of phase one reaction involves formation of conjugates with drug or its metabolites formed in phase 1reaction. The conjugate is formed with an endogenous substance such as carbohydrates and amino acids.



POINT : 1 The process of converting lipophilic (fat soluble) chemicals, which are readily absorbed from the gastrointestinal tract and other sites, into hydrophilic (water soluble) chemicals, which are readily excreted in urine or bile. Exception : Acetylation and methylation: can actually decrease the water solubility of certain xenobiotics

POINT : 2The biotransformation of xenobiotics is catalyzed by various enzyme systems that can be divided into four categories

Based on the reaction they catalyze: 1. Hydrolysis (e.g., carboxylesterase) 2. Reduction (e.g., carbonyl reductase) 3. Oxidation (e.g., cytochrome P450) 4. Conjugation (e.g., UDP-glucuronosyltransferase)


Exceptions to Point 2. Hydrolysis of certain carboxylic and phosphoric acid esters, reduction of sulfoxides to sulfides (e.g., rabeprazole), isomerization involving enolketo tautomerization (e.g., thalidomide) Conjugation of certain xenobiotics with glutathione can occur nonenzymatically at an appreciable rate.

Certain reactions are catalyzed by gastric acid, such as the hydrolysis of esters and the conversion of indole-3-carbinol to a dimer that is a potent agonist of the aryl hydrocarbon receptor (AhR) and consequently, an inducer of various enzymes including ytochrome P450 enzymes (CYP1A1, 1A2, 1B1, and 2S1).

POINT : 3In general, individual xenobiotic-biotransforming enzymes are located in a single organelle. Two sub cellular organelles are quantitatively the most important: the endoplasmic reticulum and the cytosol. The phase I oxidative enzymes : endoplasmic reticulum. Phase II enzymes: cytosol However, some enzymes are listed with two or more subcellular locations. In such cases, the enzyme name generally refers to two or more enzymes, each with its own distinct subcellular location.

Eg: Epoxide hydrolase located in microsomes is a different enzyme from the epoxide hydrolase located in cytosol (i.e., they are distinct gene products).

POINT : 4 In general, xenobiotic Biotransformation: by a limited number of enzymes with broad substrate specificities. Eg: CYP2D6 and CYP3A4metabolize over half the orally effective drugs in current use The broad/overlapping substrate specificities of xenobiotic biotransforming enzymes preclude the possibility of naming the individual enzymes after the reactions they catalyze (which is how most other enzymes are named)..

Enzymes naming based on the primary amino acid sequence of the individual enzymes. The same name across all mammalian species or named in a species-specific manner. Eg: CYP1A1, CYP1A2, CYP1B1, so named in all mammalian species Cytochrome P450 enzymes in CYP2, CYP3, and CYP4 families are named in a species-specific manner. (convention of using italic and normal letters to distinguish between the gene and gene products (mRNA and protein) lower case letters to designate mouse genes and gene products )

HOWEVER The amino acid sequence may differ among individuals, which can give rise to differences in rates of drug metabolism. A variant form of a xenobiotic-biotransforming enzyme (known as an allelic variant or an allelozyme) has diminished enzymatic activity compared with that of the wild-type enzyme, although this is not always the case . The impact of amino acid substitution(s) on the catalytic activity of a xenobiotic biotransforming enzyme may be substrate dependent, such that an allelic variant may interact normally with some substrates (and inhibitors) but interact atypically with others

POINT : 5 Hydrolysis, reduction, and oxidation expose or introduce a functional group (such as OH, NH2, SH, or COOH) that can be converted to a water-soluble conjugate reaction enzyme or specific reaction localization Hydrolysis, reduction, and oxidation: Phase 1 reactions - that resulted in either a decrease or increase in xenobiotic toxicity Conjugation reactions : Phase 2 reactions. - that resulted in only a decrease in toxicity


First : xenobiotic undergoes oxidation after it has been conjugated (phase 2 precedes Phase 1 metabolism). Eg: gemfibrozil : onjugated with glucuronic acid before it undergoes oxidation by cytochrome P450 (Ogilvie et al., 2006). Second: xenobiotics that are conjugated directly. Eg: acetaminophen is conjugated directly with glucuronic acid and, to a lesser extent, sulfonic acid

Point 5 contd Third : Phase 2 (detoxifying) enzymes : resulting in only detoxication is incorrect. Eg: conjugation of carboxylic acid-containing drugs with glucuronic acid to form acyl glucuronidesNSAIDS hepatotoxicity Enzymes which do not fit neatly/fit both into the Phase 1 or Phase 2 category. Epoxide hydrolase,Phase 1 enzyme ( it introduces a functional group (-OH) for subsequent conjugation reactions) or Phase 2 enzyme ( catalyzes the addition of water to aliphatic epoxides and arene oxides that are often formed by cytochrome P450.)

POINT : 6 Not all biotransformation reactions are catalyzed by the mammalian enzymes as listed Exceptions: Reactions catalyzed by gut microflora (largely anaerobic bacteria in the colon) Kinase and alkaline phosphatase ( anti HIV drug zidovudine- )not usually considered to be xenobiotic-biotransforming enzymes.Endobiotic metabolising enzymes

POINT : 7 xenobiotics : biotransformed by the so-called endobioticmetabolizing enzymes (Point 6) Certain endobiotics : biotransformed by the so-called xenobiotic-metabolizing enzymes. Eg: cytochrome P450 enzymes, also contribute to the hepatic catabolism of steroid hormones, UDP-glucuronosyl transferases that conjugate xenobiotics also glucuronidate bilirubin, thyroid hormones, and steroid hormones. Benzoic acid, a xenobiotic, is conjugated with glycine , and so are bile acids (endobiotics). Certain leukotrienes are glutathione conjugates.

Point 6 and 7 No clear-cut distinction between endobiotic- and xenobiotic-biotransforming enzymes. The human genome project : once thought to be two distinct enzymes, (involved in the metabolism of endobiotics and xenobiotics) are in fact one and the same enzyme. For example, the microsomal enzyme known as 11hydroxysteroid dehydrogenase is identical to the xenobiotic-metabolizing enzyme known as microsomal carbonyl reductase.

POINT : 8 Several xenobiotic-biotransforming enzymes are inducible, meaning their expression can be increased (upregulated) usually in response to exposure to high concentrations of xenobiotics. Induction is mediated by ligand-activated receptors (socalled xenosensors) that are activated by xenobiotics (ligands) to DNA-binding proteins that upregulate the transcription of various genes encoding xenobiotic-biotra