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Metabolism of drug

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  • Where the metabolite is more active (Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin)Where the metabolite is toxic (acetaminophen)Where the metabolite is carcinogenic
  • mEH and sEH are microsomal and soluble epoxide hydrolase. UDP, uridinediphosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate“Microsomes” form in vitro after cell homogenization and fractionation of ERRough microsomes are primarily associated with protein synthesisSmooth microsomes contain a class of oxidative enzymes called
  • The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.
  • The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.
  • The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.
  • The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.
  • The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.
  • The activity of these enzymes requires both a reducing agent (nicotinamide adenine dinucleotide phosphate [NADPH]) and molecular oxygen; in a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water.

Transcript

  • 1. Dr.Asad UllahAsadUllahPharmD@gmail.comMetabolism ofDugs:biotransformation
  • 2. 2
  • 3.  Structural modification of drug inside thebody It is the mechanism of eliminationforeign and undesirable compounds frombody and the controls of level ofdesirable compound such as vitamin inthe body. Most often this process entails a loss ofbiological activity and an increase inhydrophilicity ,promoting elimination viathe renal routeMetabolism ofDrugs:biotransformation 3
  • 4. Metabolism of Drugs:biotransformation 4
  • 5.  Purpose◦ Converts lipophilic to hydrophilic compounds◦ Facilitates excretion◦ Prevention of drug accumulation Consequences◦ Changes in PK characteristics◦ Detoxification◦ Metabolic activationMetabolism of Drugs:biotransformation 5
  • 6.  Inactivatione.g: Amphetamine to Phenylacetone, Phenobarbital tohydroxyphenobarbitol ActivationCodeine to morphine,imipramine to Despiramine Reactive IntermediateParacetamol to Imidoquinone or N-hydroxylated metabolite Prodrug to active metaboliteAzathioprine to Mercaptopurine, Prednisone to prednisoloneMetabolism of Drugs:biotransformation 6
  • 7. Liver>Lungs>Kidney>Intestine>Placenta>Adrenals>SkinMetabolism of Drugs:biotransformation 7
  • 8. Hepatic microsomal enzymes(oxidation, conjugation)Extrahepatic microsomal enzymes(oxidation, conjugation)Hepatic non-microsomal enzymes(acetylation, sulfation,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)8
  • 9. 9Phase I Phase IITypes of reactions HydrolysisOxidationReductionConjugationsIncrease inhydrophilicitySmall LargeGeneral mechanism Exposes functionalgroupPolar compound addedto functional groupConsquences May result inmetabolic activationFacilitates excretion
  • 10. Phase I andPhase IImetabolism ofPhenytoin10
  • 11.  The phase 1 enzymes lead to the introductionof functional groups, resulting in amodification of the drug, such that it nowcarries an –OH, -COOH, or NH2 group. The addition of functional groups does littleto increase the water solubility of the drug,but can dramatically alter the biologicalproperties of the drug11
  • 12.  Also called as Non-synthetic Reactions/Functionalization Reaction.1. OXIDATION2. REDUCTION3. HYDROLYSIS The primary objectives are:◦ Increase in hydrophilicity◦ Redeuction in stability◦ Facilitation of conjugation12
  • 13. ENZYMES:OxygenasesREACTIONCytochrome P450 C and O oxidation, dealkylation,othersFlavin Monooxygenases oxidases(FMO)N, S, and P oxidationEpoxide hydrolases mEH,sEH Hydrolysis of epoxides13
  • 14.  The CYPs are a superfamily of enzymes, allof which contain a molecule of heme that isnoncovalently bound to the polypeptidechain At least 74 gene families 14 ubiquitous in all mammals CYP1, 2, 3, involved in detoxification oflipophilic, or nonpolar substances Other CYP families involved in metabolismof endogenous substances, such as fattyacids, prostaglandins, steroids, and thyroidhormones14
  • 15. 15
  • 16. 16
  • 17.  6 Families of FMOs,FMO 3 mostly in liver Similar to CYPs, the FMOs are expressed athigh levels in the liver and are bound to theendoplasmic reticulum, a site that favorsinteraction with and metabolism ofhydrophobic drug substrates. Not easily induced or inhibited unlike toCYPs.17
  • 18.  Soluble epoxide Hydrolase (sEH) ,microsomal epoxide hydrolase (mEH) carry out hydrolysis of epoxides producedby CYPs. Epoxides are highly reactive electrophilesthat can bind to cellular nucleophiles foundin protein, RNA, and DNA, resulting in celltoxicity and transformation.18
  • 19.  Phase II is the true “detoxification” step in themetabolism process. Also called as Synthetic or conjugate reactions. These involve transfer of suitable endogenousmoiety such as glucuronic acid, sulphate,glycine in the presence of enzyme transferaseto drugs or metabolites of phaseI reactions. This leads to formation of highly polar, readilyexcretable and phamacologically inertconjugates.19
  • 20. Enzymes (“Transferses) ReactionSulfotransferases (SULT) Addition to sulphateUDP-glucuronosyltransferases(UGTAddition to glucoronic acidGlutathione-S-transferases (GST) Addition to glutathionN-acetyltransferases (NAT) Addition to acetyl groupMethyltransferases (MT) Addition to methyl group20
  • 21.  Phase II reactions are real drugdetoxication pathways because :◦ Conjugates are absolutely free ofpharmacological activity◦ Highly polar conjugates and thus easily excretedeither in bile or urine.◦ Tissue reactive and carcinogenic metabolites arerendered harmless by conjugation with moietieslike glutathione.21
  • 22. “The phenomenon of increased drugmetabolising ability of the enzymes (especiallyof microsomal monooxygenase system) byseveral drugs and chemicals is called asenzyme 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 reticulum22
  • 23. “ A decrease in the drug metabolizingability of an enzyme is called as enzymeinhibition.”Types: Direct ;◦ Competitive◦ Non-competitive◦ Product inhibition Indirect◦ Repression (supressing)◦ Altered physiology23
  • 24. 24
  • 25.  Goodman & Gilmans The Pharmacological Basis ofTherapeutics, 11th Edition Basic & Clinical Pharmacology, 11th EditionBertram G. Katzung, Susan B. Masters, Anthony J. Trevor Color atlas of Pharmacology 3rd Edition Casarett and Doull’s Toxicology, The Basic Sciences ofPoisons, 5th Edition, Klassen, Amdur & Doull (eds), MacmillanPublishing Co. WWW.Medscpe.com25
  • 26. THANKSKAMSHAMINDASHUKRIA26