Phase 1 metabolism.pptx

Metabolism of drugs

1. Presented by- Parimal Hadge PE/2019/311 PC-610 1

2. Contents 25-01-2021 2

3. Drug metabolism is the  metabolic breakdown of  drugs  by living organisms , usually through specialized  enzymatic   systems. Xenobiotic metabolism is the set of  metabolic pathways   that modify the chemical structure of  xenobiotics , which are compounds foreign to an organism's normal biochemistry Significance: The reasons for studying and understanding the various metabolic pathways is 1)They help in determining the duration and intensity of pharmacological action of the drug 2)Help in understanding the hazardous drug interactions 3)These pathways are also important in environmental science w ith the xenobiotic metabolism of  microorganism  determining whether a pollutant will be broken down during  bioremediation (treat contaminated media by altering environmental conditions to stimulate microbe growth and degrade target pollutant) , or  persist  in the environment 4)Provides opportunity for synthesizing prodrugs . Introduction 25-01-2021 3

4. Phase-I(Non-synthetic) drug metabolism The metabolism of xenobiotics is often divided into three phases:- modification, conjugation, and excretion. In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalyzed by the   cytochrome P-450-dependent mixed-function oxidase system . These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme: 25-01-2021 4

5. Phase I reactions (also termed non-synthetic reactions) may occur by  oxidation ,  reduction ,  hydrolysis ,  cyclization ,  de-cyclization . The addition of oxygen or removal of hydrogen, are carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a  cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. Some of the classes of pharmaceutical drugs that utilize this method for their metabolism include  phenothiazines ,  paracetamol , and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an  endogenous substrate combines with the newly incorporated functional group to form a highly  polar conjugate. A common Phase I oxidation involves conversion of a C-H bond to a C-OH . This reaction sometimes converts a pharmacologically inactive compound (a  prodrug ) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one ( toxification ) 25-01-2021 5

6. Oxidation Cytochrome P450(CYPs): These are a  superfamily  of  enzymes  containing  heme  as a  cofactor  that function as  monooxygenases . In mammals, these proteins oxidize  steroids ,  fatty acids , and  Xenobiotics , and are important for the  clearance  of various compounds, as well as for hormone synthesis and breakdown. CYPs are, in general, the terminal oxidase  enzymes  in  electron transfer chains, broadly categorized as  P-450 containing systems . The term "P450" is derived from the  spectrophotometric  peak at the  wavelength  of the  absor ption maxima of the enzyme (450  nm ) when it is in the  reduced  state and complexed with  carbon monoxide . Most CYPs require a protein partner to deliver one or more  electrons  to reduce the  iron  (and eventually molecular  oxygen ) 25-01-2021 6

7. Based on the nature of the electron transfer proteins, CYPs can be classified into several groups Microsomal P450 systems :In this electrons are transferred from  NADPH  via  cytochrome p450 reductase .   Cytochromeb 5 (cyb 5 ) can also contribute reducing power to this system after being reduced by  cytochrome b 5 reductase . Mitochondrial P450 systems: Employ adrenodoxin reductase and adrenodoxin to transfer electrons from NADPH to p450 Bacterial P450 systems: Employ Ferridoxin reductase and ferredoxin to transfer electrons to P450. The most common reaction catalyzed by cytochromes P450 is a Monoxygenase reaction, e.g., insertion of one atom of oxygen into the aliphatic position of an organic substrate (RH) while the other oxygen atom is  reduced  to water as observed in the general catalytic cycle 25-01-2021 7

8. Possibl e mechanisms for Oxidation of Ethanol and Acetaldehyde by P450 2E1 by FeO 3+ H . ‚ Abstraction 25-01-2021 8

9. Oxidative N-Dealkylation of N-Ethyl N-methylaniline by P450 2B1 25-01-2021 9

10. CYP 3A4 and 3A5 hydroxylation and oxidation 25-01-2021 10

11. Reduction Flavoproteins are majorly involved in reduction of endogenous substances Although P450s do not participate in biological reductions of endogenous substrates to the extent that flavoproteins do, the diversity of reduction reactions catalyzed by P450s is still considerable Nitrogen oxides are reduced by P450s and in many cases, by other enzymes as well. The list of substrates that can be reduced includes N-oxides, nitroxides, hydroxylamines , nitro groups, and C- and N-nitroso compounds Reduction of Nitro Compounds by P450s Reductive Dechlorination of CCl 4 and Reaction of Trichloromethyl Radical with O 2 25-01-2021 11

12. Reduction of Zonisamide 25-01-2021 12

13. Hydrolysis Esterases, amidases and epoxide hydrolases are some of the enzymes which catalyze via hydrolytic reactions. These class of enzymes are referred to as hydrolases Esterases: An  esterase  is a  hydrolase enzyme   that splits  esters  into an  acid  and an  alcohol Esterases cleave ester bonds in lipids and phosphatases cleave phosphate groups off molecules. An example of crucial esterase is acetylcholine esterase, which assists in transforming the neuron impulse into acetic acid after the hydrolase breaks the acetylcholine into choline and acetic acid Amidases: This enzyme belongs to the family of  hydrolases , those acting on carbon-nitrogen bonds other than peptide bonds, specifically in linear amides This enzyme participates in 6  metabolic pathways :  urea cycle and metabolism of amino group ,  phenylalanine metabolism ,  tryptophan metabolism , cyanoamino acid metabolism , benzoate degradation, and  styrene degradation 25-01-2021 13

14. Epoxide hydrolases  (EH's), also known as epoxide hydratases, are  enzymes  that metabolize compounds that contain an  epoxide  residue; they convert this residue to two  hydroxyl  residues through a  dihydroxylation  reaction to form  diol  products The hydrolases are distinguished from each other by their substrate preferences and, directly related to this, their functions General mechanism of amidase action 25-01-2021 14

15. Epoxide hydrolase metabolism 25-01-2021 15

16. References Goodman and Gilman, Pharmacological basis of Therapeutics, 12 th edition , Laurence l. Bruton. Essentials of Medical Pharmacology , K.D. Tripathi, 7 th edition JP publishers, New Delhi. Drug metabolism by S.P.Merkey , NIH, accessed on internet on 24-01-2021. 25-01-2021 16

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