Drug metabolism

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Drug Elimination Metabolism:

Drug Elimination Metabolism Guided by: Dr V M Motghare Prof & Head Presented by ; Dr Rushikesh Deshpande JR I Department of Pharmacology S R T R Medical College, Ambajogai

Drug Elimination :

Drug Elimination Termination of drug effect is by the process of drug elimination which involves mainly two processes: Metabolism: predominantly in the liver and kidney. Excretion of unchanged drug or its metabolite predominantly by kidney. Excretion also takes place in the gut, skin, lungs, sweat glands, breast and salivary glands. In addition there is a third process of termination of drug action i.e. process of redistribution of drug. 2

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The onset of pharmacological response depends on: Drug absorption Drug distribution The duration and intensity of action depends upon: Tissue redistribution of drug and The rate of elimination 3

Drug Metabolism (Biotransformation):

Drug Metabolism (Biotransformation) 4

Fate of drug :

Fate of drug “Alteration of a drug within a living organism is known as Bio-transformation” “The term Biotransformation is the process of alteration in the structure of drug molecule in the body especially liver.” 5

Need for drug biotransformation:

Need for drug biotransformation Drugs are xenobiotics which enter the body by virtue of their lipophilicity . For effective absorption, a drug needs to be sufficiently lipid-soluble but this same physicochemical property enables it to bypass excretion. Only water soluble agents undergo renal excretion, whereas lipid-soluble substances are passively reabsorbed from the renal tubules into the blood after glomerular filtration 6

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Hence to prevent drug accumulation in the body and toxicity precipitation, the body is armed with the metabolic system which transforms the water insoluble, lipophilic , nonpolar drugs into the polar and water-soluble products to get easily excreted by the kidneys. 7

Effects of Biotransformation:

Effects of Biotransformation 8 Active Inactive Amphetamine Phenylacetone Phenobarbital Hydroxyphenobarbital Phenytoin p- hydroxyphenytoin Salicylic Acid Salicyluric acid

Effect of biotransformation :

Effect of biotransformation Active Active Amytriptyline Nortryptyline Imipramine Desipramine Codeine Morphine Phenylbutazone Oxyphenbutazone Diazepam Dysmethyl diazepam or Oxazepam Digitoxin Digoxin Chloral hydrate Trichloroethanol Morphine morphine 6-glucuronide Allopurinol alloxanthine 9

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Active Reactive intermediates Isoniazid Tissue acetylating intermediate Paracetamol Imidoquinone or N- hydroxylated metabolite 10 Effect of biotransformation

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Active  Active Useful : L-dopa  Dopamine Toxic : Parathion  Paroxone Other exaples : Chloral hydrate trichloroethanol Morphinemorphine 6-glucuronide Allopurinol  alloxanthine procainamideN acetyl procaiamide - Diazepam oxazepam - Digitoxindigoxin - Imipramine  desipramine 11

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Active  Reactive intermediates More active : Diazepam  Oxazepam Different activity : Pethidine  Norpethidine (CNS depressant) (CNS stimulant) 12

Prodrug :

Prodrug Prodrug ; Few drugs are inactive as such and they need conversion in the body to one or more active metabolite. Prodrugs improve oral absorption, decrease first pass effect and reduce toxicity. Sometimes the products are highly reactive and result in toxicity. e.g. Paracetamol  N hydroxylated compound hepatotoxic 13

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Inactive ( Prodrug )  Active 14 Inactive Active L - dopa Dopamine Prednisone Prednisolone Talampicillin Ampicillin Cylcophosphamide Aldophosphamide Dipivefrine Epinephrine Proguanil Cycloguanil Bacampicillin Ampicilin Sulphasalazine 5-aminosalicylic acid Sulindac Sulphide metabolite Fluorouracil Fluorouridine monophosphate

Prodrugs :

Prodrugs Inactive Active Azathiorprine Mercaptopurine Estramustine Normustine Acylcovir Acycloguanosine Carfecillin Carbenecillin Indanylcarbenicilin Carbenecillin Enalapril Enalaprilat Pivampicillin Ampicillin Cholecalciferol 10-hydroxy cholecalciferol Ibutard Terbutaline Benorylate Salicylic acid and paracetamol 15

Metabolic Pathway Of Paracetamol:

Metabolic Pathway Of Paracetamol 16 Paracetamol 95% Conjugation N –OH- Paracetamol GS- Paracetamol Hepatocellular Protein HEPATOTOXICITY Non toxic Reactive GSH+ Non Reactive Cyt P 450

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Change in pharmacological activity. 17 Iproniazid (Antidepressant) Isoniazid (Antitubercular) Diazepam (tranquilizer ) oxazepam (anticonvulsant)

Drug metabolizing organs :

Drug metabolizing organs Liver > Lungs > Kidneys > Intestine > Placenta > Adrenals > Skin. 18

Drug Metabolizing Enzymes:

Hepatic microsomal enzymes (oxidation, conjugation) Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic non- microsomal enzymes ( acetylation , sulfation,GSH , alcohol/ aldehyde dehydrogenase , hydrolysis, ox/red) Drug Metabolizing Enzymes 19

Microsomal enzyme system:

Microsomal enzyme system Microsomes are derived from rough endoplasmic reticulum. They catalyse a number of oxidative, reductive and hydrolytic and glucuronidation reactions. 20

Non-microsomal enzymes:

Non- microsomal enzymes These are present in Soluble form in cytoplasm and mitochondria. They are non-specific in nature. They carry out few oxidative, reductive, hydrolytic reactions along with conjugation reactions ( except glucuronidation ). 21

Chemical Pathways of Drug Biotransformation:

Chemical Pathways of Drug Biotransformation 22

Historical aspects:

Historical aspects The year 1966 is considered as an important landmark in the field of ‘Drug metabolism research’ due to following novel discoveries: The existence of multiple isoenzymes of cytochrome P-450, their basic functions and characteristics. The clinical implications of enzyme induction to drug therapy in various diseases. The hepatotoxic potential of environmental toxins following the devastating outbreak of “Epping Jaundice” from contamination of flour with diamino-diphenylmethane . Inception of barbiturate therapy in the treatment of unconjugated hyperbilirubinemia by the Drug Metabolism Group of King’s Liver Unit-UK. 23

Evolution of Drug Metabolism As a Science Post WWII Pioneers :

Evolution of Drug Metabolism As a Science Post WWII Pioneers Richard Tecwyn Williams – Great Britain 1942, worked on the metabolism on TNT with regard to toxicity in munitions workers; due to the war he assembled teams to work on metabolism of sulfonamides, benzene, aniline, acetanilide, phenacetin , and stilbesterol Developed concept of Phase 1 & Phase 2 Reactions. Biotransformation involves metabolic oxygenation, reduction, or hydrolysis; result in changes in biological activity (increased or decreased) Second phase, conjugation, in almost all cases resulted in detoxication . 24

Phase I Reactions:

Phase I Reactions Also called as Non-synthetic Reactions/ Functionalization Reaction . OXIDATION REDUCTION HYDROLYSIS The primary objectives are: Increase in hydrophilicity Redeuction in stability Facilitation of conjugation. 25

Microsomal oxidation:

Microsomal oxidation Reaction Enzyme Drugs Aliphatic hydroxylation Cytochrome P 450 Phenobarbitone  p- hydroxyphenobarbitone N- Dealkylation Cytochrome P 450 Mephobarbitone  Phenobarbitone Sulpho -oxidation Cytochrome P 450 Chlorpromazine  chlorpromazine sulphoxide Deamination Cytiochrome P 450 Amphetamine  phenyl acetone 26

Cytochrome P450s:

Cytochrome P450s 27

CYPs (cytochrome P450s):

CYPs (cytochrome P450s) At least 74 gene families 14 ubiquitous in all mammals CYP1, 2, 3, involved in detoxification of lipophilic, or nonpolar substances Other CYP families involved in metabolism of endogenous substances, such as fatty acids, prostaglandins, steroids, and thyroid hormones 28

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Non-microsomal oxidation:

Non- microsomal oxidation Reaction Enzyme Drugs Deamination of MAO Cytochrome P 450 Tyramine  p hydroxy acetaldehyde Oxidation of alcohol Cytochrome P 450 Ethanol  Acetic acid 30

Microsomal reduction:

Microsomal reduction Reaction Enzyme Drugs Nitroreduction Flavin Chloramphenicol  amiochloramphenicol Azo reduction Flavin Protonsil sulphonamide Dehalogenation Flavin Halothane  trifluroethane Alcohol dehydrogenase reaction Flavin Chloral hydarte  trichloroethanol 31

Hydrolysis :

Hydrolysis Enzymes are esterase and amidase E.g. Acetyl choline , Lignocaine , Procaine, Succinyl choline . 32

Phase II reactions:

Phase II reactions Also called as Synthetic or conjugate reactions. These involve transfer of suitable endogenous moiety such as glucuronic acid, sulphate , glycine in the presence of enzyme transferase to drugs or metabolites of phaseI reactions. This leads to formation of highly polar, readily excretable and phamacologically inert conjugates . 33

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Phase II reactions are real drug detoxication pathways because : Conjugates are absolutely free of pharmacological activity Highly polar conjugates and thus easily excreted either in bile or urine. Tissue reactive and carcinogenic metabolites are rendered harmless by conjugation with moieties like glutathione. 34

Phase II reactions and their characteristics:

Phase II reactions and their characteristics Conjugation Conjugating agents Enzyme Examples Glucuronidation Glucuronic acid UDP- glucuronyl transferase Chloramphenicol , aspirin, morphine Sulphation Sulphate Sulphotransferase Adrenal, sex steroid hormones Amino acid cojugation Glycine Acyl transferase Salicylic acid, nicotinic acid Glutathione Glutathione Glutathione S transferase Acetylation Acetyl Co A N Acetyl transferase INH, Hydralazine Methylation L- methionine Methyl transferase Adrenaline, isoprenaline , histamine 35

Factors affecting metabolism :

Factors affecting metabolism Physicochemical properties of the drug Chemical factors Enzyme induction Enzyme inhibition Environmental chemicals Biologic factors Species differences Strain differences Age , sex Diet Altered physiological factors Pregnancy Hormonal imbalance Disease state Temporal factors Circadian rhythm Circannual rhythm 36

Physicochemical properties of the drug :

Physicochemical properties of the drug Molecular size and shape pKa Acidity/ basicity Lipophilicity Stereochemical nature of drug e.g. Verapamil 37

Chemical factors : Enzyme Induction:

Chemical factors : Enzyme Induction “The phenomenon of increased drug metabolising ability of the enzymes (especially of microsomal monooxygenase system) by several drugs and chemicals is called as enzyme induction.” Mechanism : Increased liver size, blood flow Increased both total and microsomal protein content Increased stability of enzymes Increase synthesis of Cytochrome P-450 Proliferation of smooth endoplasmic reticulum 38

Inducers of drug metabolizing enzyme system:

Inducers of drug metabolizing enzyme system 39 Inducers Drugs with enhanced metabolism Barbiturates Coumarins , phenytoin , cortisol , testesterone , oral contraceptives Alcohol Pentobarbital, coumarins , phenytoin Phenytoin Cortisol , coumarins , oral contraceptives, tolbutamide Rifampicin Coumarins , oral contraceptives, tolbutamide Cigarette smoke Nicotine, amino azo dyes. Pyridoxine L dopa Grieofulvin Warfarin Chronic ethanol intake Ethanol itself, warfarin , tolbutamide , barbiturates, diazepam

Significance Of Enzyme Induction:

Significance Of Enzyme Induction Tolerance e.g. Phenobarbitone : increases enzymes which causes its own metabolism. 2. Utility in the treatment: e.g. Phenobarbitone is useful in neonatal jaundice. It stimulates the acivity of enzyme glucuronyl transferase . This leads to increased conjugation of bilirubin which controls the jaundice. 40

Significance Of Enzyme Induction:

Significance Of Enzyme Induction 3. Precipitation of some disorders: Phenobarbitone causes neurological complication and even death in patients with acute intermitant porphyria 4. Drug interaction : when 2 drugs are combined together and one drug is causing enzyme induction then it will increase the metabolism of other drug. e.g. Phenobarbitone , Rifampicin can increase metabolism of oral contraceptives. Phenobarbitone increases the metabolism of Phenytoin and oral anticoagulants. 41

Clinical relevance of enzyme induction :

Clinical relevance of enzyme induction Unwanted pregnancy : if oral contraceptive pills are used along with inducers like rifampicin. Patients on barbiturates would need higher doses of oral anticoagulants, like warfarin . Conversely, if barbiturates are suddenly withdrawn but the doses of anticoagulants are proportionately not reduced, the patient may start bleeding. Phenytoin accelerate metabolism of Vit D3 leading to osteomalacia . Barbiturates, usually enhance their own metabolism leading to the development of Pharmacokinetic (metabolic)tolerance. 42

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Enzyme induction can lead to drug toxicity. E.g. ethanol drinkers have more probability of developing hepatotoxicity from paracetamol overdose or even with therapeutic doses due to increased production of N-acetyl-p- benzoquinone , a hepatotoxic metabolite of paracetamol . Therapeutic benefits: Phenobarbitone can be used for treatment of neonatal jaundice. 43

Enzyme inhibition :

Enzyme inhibition “ A decrease in the drug metabolizing ability of an enzyme is called as enzyme inhibition.” Types: Direct ; Competitive Non-competitive Product inhibition Indirect Repression Altered physiology 44

Enzyme inhibitors and drugs affected by them:

Enzyme inhibitors and drugs affected by them Inhibitors Dugs with decreased metabolism MAO inhibitors Barbiturates, tyramine Coumarins Phenytoin Allopurinol 6-mercaptopurine PAS Phenytoin Cimetidine Phenytoin Valproate Phenytoin, Phenobarbital, Primidone Erythromycin Theophylline , warfarin , carbamazepine , cyclosporine 45


Contd… Inhibitors Dugs with decreased metabolism Ciprofloxacin group (except ofloxacin ) Theophylline Chloramphenicol Terfenadine , Tolbutamide,Phenytoin , Warfarin Verapamil , Diltiazem Theophylline,Carbamazepine,cyclosporine Disulfiram Alcohol , Phenytoin, warfarin . 46

Clinical relevance :

Clinical relevance Potentially adverse consequences: Unexpected nausea and vomiting due to theophylline with concurrently administered chloramphenicol . Enhanced bleeding tendancy with dicumarol when administered with cimetidine . Severe respiratory depression with morphine when given with MAOIs (mono-amine oxidase inhibitor) Severe ataxia and drowsiness with phenytoin in combination with dicumarol or chloramphenicol . Precipitation of cardiac arrythmias with terfenadine when given in combination with cholamphenicol . 47


Contd… B) Therapeutically Beneficial Consequences: Increased accesibility of l- dopa in brain when given along with carbidopa (L- aminoacid decarboxylase inhibitor.) Aversion of alcohol after prior administration of disulfiram ( aldehyde dehydrogenase inhibitor) Reversal of skeletal muscle paralysis due to d- tubocurarine by neostigmine ( acetylcholinesterase reversible inhibitors) 48

Environmental chemicals :

Environmental chemicals Halogenated pesticides like DDT and PAH contained in cigarette smoke have enzyme induction effect. Organophosphate insecticides and heavy metals like mercury, tin, nickel, cobalt and arsenic inhibit drug metabolizing ability of enzymes. 49

Biological factors : species variation:

Biological factors : species variation Species variation are observed in both phase I and II reactions. E.g. Men, rabbit: amphetamine and ephedrine are metabolized by oxidative deamination as compared to aromatic oxidation in rats. 50

Strain differences:

Strain differences Differences observed in the metabolism of a drug among different races are called as ethnic variations. e.g. polymorphism : acetylation of isoniazid. 51

Sex differences :

Sex differences Attributed to sex hormones. e.g. male wistar rats have greater drug metabolising capacity In humans : women metabolise benzodiazepines slowly than men. 52

Age :

Age Upto 2 months : slow biotransformation as microsomal enzyme system is not fully developed. E.g. caffeine half life of 4 days in neonate in comparison to 4 hr in adults. 2 months – 1 year : enzyme activity increases. 1 yr – 12 yr : more rapid than adults. Elderly ; decreased metabolism as a result of decreased liver size, microsomal enzyme activity. 53

Diet :

Diet Enzyme synthesis is promoted by protein diet, high protein-carbohydrate ratio. Decreased metabolism is seen with fat free diet, grapefruit juice, starvation etc. Alcohol: short term decrease followed by increase in the enzyme activity. 54

Altered physiological state : pregnancy:

Altered physiological state : pregnancy Maternal drug metabolising activity is reduced in later stages of pregnancy. This was attributed to high levels of steroid hormones in circulation in pregnancy. Higher rate of hepatic metabolism of anticonvulsants during pregnancy is related to enzyme induction by progesterone. 55

Hormonal imbalance:

Hormonal imbalance Impaired drug metabolism has been shown after adrenalectomy , thyroidectomy and alloxan induced diabetes in animals. Stress related changes in ACTH levels also influence drug biotransformation. 56

Bioactivation and tissue toxicity:

Bioactivation and tissue toxicity “Formation of highly reactive metabolites(from relatively inert chemical compounds) which interact with the tissues to precipitate one or more of the several form of toxicities such as carcinogenesis and teratogenesis is called as bioactivation or toxicological activation.” e.g. Benzopyrene : aromatic epoxidation : lung cancer Aflatoxin B1 : olefin epoxidation : Hepatic cancer. Thalidomide : hydrolytic cleavage of lactam : Teratogenesis 57


References Study notes by Dr V M Motghare, Prof & Head, Dept Of Pharmacology. Principals of Pharmacology- Sharma & Sharma Biopharmaceutics – Brahmankar and Jaiswal . Internet. 58

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