Metabolism of drug

2,444 views

Published on

0 Comments
7 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,444
On SlideShare
0
From Embeds
0
Number of Embeds
4
Actions
Shares
0
Downloads
0
Comments
0
Likes
7
Embeds 0
No embeds

No notes for slide
  • 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.
  • Metabolism of drug

    1. 1. Dr.Asad UllahAsadUllahPharmD@gmail.comMetabolism ofDugs:biotransformation
    2. 2. 2
    3. 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. 4. Metabolism of Drugs:biotransformation 4
    5. 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. 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. 7. Liver>Lungs>Kidney>Intestine>Placenta>Adrenals>SkinMetabolism of Drugs:biotransformation 7
    8. 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. 9. 9Phase I Phase IITypes of reactions HydrolysisOxidationReductionConjugationsIncrease inhydrophilicitySmall LargeGeneral mechanism Exposes functionalgroupPolar compound addedto functional groupConsquences May result inmetabolic activationFacilitates excretion
    10. 10. Phase I andPhase IImetabolism ofPhenytoin10
    11. 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. 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. 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. 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. 15
    16. 16. 16
    17. 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. 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. 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. 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. 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. 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. 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. 24
    25. 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. 26. THANKSKAMSHAMINDASHUKRIA26

    ×