Drug Metabolism Lecture Notes PDF

Drug Metabolism Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Lec. 1 Faculty of Pharmacy, Cairo University Course Outline 1. Metabolism Introduction. 2. Phase I Reactions. a. Hydrolysis. b. Reduction. c. Oxidation. 3. Phase II Reactions. 2 Phases o...

Drug Metabolism Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Lec. 1 Faculty of Pharmacy, Cairo University Course Outline 1. Metabolism Introduction. 2. Phase I Reactions. a. Hydrolysis. b. Reduction. c. Oxidation. 3. Phase II Reactions. 2 Phases of Drug Action Pharmaceutical Phase: Disintegration, release of the drug, & its dissolution. Pharmacokinetic Phase: Absorption from the GIT into the blood supply, & the various factors that affect a drug’s survival & progress. Pharmacodynamic Phase: Mechanism of drug interaction with its molecular target & the resulting pharmacological effect. 3 Factors to Consider in Pharmacokinetics (PKs) Pharmacokinetic Phase: Absorption from the GIT into the blood supply, and the various factors that affect a drug’s survival & progress. Absorption log P, pKa, solubility, dissolution rate. Distribution Solubility, stability & plasma protein binding. Metabolism Age, sex, genetic factors, lifestyle, disease state. Excretion Water solubility. 4 1. Drug Metabolism Drug Metabolism (Biotransformation) Chemical reactions that are responsible for the conversion of the drug to its metabolites which are usually more water soluble than the parent drug & are usually excreted in urine. Xenobiotics [drug & foreign compounds to body] are excreted either after biotransformation or unchanged. Metabolism The drugs are rendered more water soluble, less reabsorbed → more excreted → Detoxification. Target 6 Drug Metabolism Possibilities 1. Active drug → Inactive metabolites [Most common pathway]. 2. Active drug → Active metabolite(s) [Co-activation] 7 Drug Metabolism Possibilities 3. Active drug → Toxic metabolites [Metabolic toxicity] 4. Inactive drug → Active metabolite(s) [Prodrugs] 8 Drug Metabolism Possibilities 5. Active parent drug → Active metabolite having a different pharmacological action 9 Sites of Drug Metabolism In liver [ Hepatic] Extra-Hepatic The main site of metabolism as it’s As kidney, lungs, intestinal full of metabolizing enzymes mucosa, adrenal glands, and well perfused organ. placenta, & brain. 1st Pass Effect: Intestinal bacterial flora in the Orally administered drugs [most intestine play role in drug of drugs] → pass through the metabolism. liver before being distributed to systemic circulation & reaching the site of action. 10 Sites of Drug Metabolism ❑ Orally administered drugs pass through the liver before reaching the systemic circulation & thus subjected to metabolism (First pass effect). ❑ Drugs with extensive first pass metabolism are taken by other routes [sublingual nitroglycerin] or taken with a higher dose. 11 Drug Metabolism Phases Phase I Phase II Metabolism Metabolism Functionalization Conjugation Reactions Reactions 12 2. Phase I Reactions Functionalization Reactions Phase I Reactions ❑ Render the drug more polar (less lipid-soluble), therefore presenting reduced ability to penetrate tissues & less renal tubular reabsorption than the parent drug. ❑ By introduction of a polar functionalgroup (Handle Group) e.g., OH, COOH, NH2, SH into the molecule. ❑ This can be achieved by: ▪ Direct introduction of a polar group (e.g., aromatic hydroxylation). ▪ Modification of existing functionalities (reduction of aldehydes & ketones). ▪ Expose a functional group for phase 2 reactions (hydrolysis of ester). 14 Phase I Phase I Reactions Oxidation Reduction Hydrolysis Reactions Reactions Reactions Aromatic/ olefinic. Aldehyde/ketone. Esters. Benzylic/ Allylic. Nitro. Amides. Aliphatic/Alicyclic. Sulfone. C  to C=O. Azo. Aldehyde/ketone. Disulfide. Aromatization. Dehalogenation. C  to heteroatom. 15 Phase I Phase I Reactions Esters Amides Hydrolysis Reactions Esters. Amides. Esterase HO H Amidase HO H HO-R H2N-R Acid Alcohol Acid Amine 16 Phase I Hydrolysis Reactions Esters’ Hydrolysis ❑Catalyzed by Esterases which are non-specific & widely distributed in liver, kidney & intestine. ❑Major pathway for esters → facile hydrolysis. ❑Hydrolytic products are alcohol & acid → contain functional groups that can be conjugated. 17 Phase I Hydrolysis Reactions Examples _ Esterase _ Amidase _ Amides are slowly hydrolyzed than Esters → longer duration N.B.: Presence of ewd groups can increase the susceptibility of both amides & esters to hydrolysis. 18 Phase I Hydrolysis Reactions Examples Esterase Amidase 19 Phase I Hydrolysis Reactions Examples Lactone is a Esterase cyclic ester Β-lactamase Lactam is a cyclic amide 20 Phase I Hydrolysis Reactions Esters Amides Enzyme Esterase. Amidase. Distribution Liver, kidney, intestine. Liver. Products Acid & alcohol. Acid & amine. Rate Rapid. Slow ( Long duration). Major or minor Major pathway. Electron withdrawing group increases the rate of Substituent effect hydrolysis. Cyclised Lactone by esterase. Lactam by lactamase. 21 Phase I Phase I Reactions Oxidation Reduction Hydrolysis Reactions Reactions Reactions Aromatic/ olefinic. Aldehyde/ketone. Esters. Benzylic/ Allylic. Nitro. Amides. Aliphatic/Alicyclic Sulfone. C  to C=O Azo. Aldehyde/ketone. Disulfide. Aromatization. Dehalogenation. C  to heteroatom. 22 Phase I Phase I Reactions Aldehyde Ketone Reduction Reactions Aldehyde/ketone. Nitro. Sulfone. Reductase Reductase Azo. Disulfide. 1ry Alcohol 2ry Alcohol 23 Phase I Reduction Reactions Aldehydes ❑ Majority of aldehydes oxidized to carboxylic acids but may be reduced to alcohols especially if attached to e-withdrawing group. 24 Phase I Reduction Reactions Ketones ❑Ketones are generally resistant to oxidation & therefore undergo reduction to secondary alcohols. 25 Phase I Phase I Reactions Nitro Sulfone Reduction Reactions Reductase Aldehyde/ketone. Nitro. Sulfone. Reductase Sulfoxide Azo. Disulfide. Reductase 1ry Amine Sulfide (Thioether) 26 Phase I Reduction Reactions Examples 27 Phase I Phase I Reactions Azo Disulfide Reduction Reactions Aldehyde/ketone. Nitro. Sulfone. Reductase Reductase Azo. Disulfide. H2N-R 1ry Amine Thiol 28 Phase I Reduction Reactions Examples Thiol 29 Phase I Reduction Reactions Aldehydes Ketones Nitro Sulfone Azo Disulfide R-CH=O R-CO-R NO2 R-SO2-R RN=NR’ R-S-S-R’ Enzyme Reductase Products 2ry N=O RSH + R-SO-R RNH2 + 1ry alcohol alcohol →NHOH R’SH →R-S-R R’NH2 (Isomers) →NH2 (Thiol) Major Minor if or there is minor ewd group (otherwise Major oxidation is major pathway) 30 BREAK Phase I Phase I Reactions Oxidation Reduction Hydrolysis Reactions Reactions Reactions Aromatic/ olefinic. Aldehyde/ketone. Esters. Benzylic/ Allylic. Nitro. Amides. Aliphatic/Alicyclic Sulfone. C  to C=O Azo. Aldehyde/ketone. Disulfide. Aromatization. Dehalogenation. C  to heteroatom. 32 Phase I Phase I Reactions ❑ The most common reaction for xenobiotics. Oxidation ❑ Catalyzed by a group of membrane-bound mono-oxygenase Reactions enzymes found in endoplasmic reticulum of liver & other Aromatic/ olefinic. Benzylic/ Allylic. extra- hepatic tissues. Aliphatic/Alicyclic ❑ These mono-oxygenases are called: Cytochrome P-450 [CYP- C  to C=O Aldehyde/ketone. 450]. Aromatization. ❑ CYP-450 is a large family of hemeprotein enzymes and play Dehalogenation. C  to heteroatom. a key role in the oxidative transformation of endogenous & exogenous molecules. 33 Phase I Phase I Reactions Oxidation ❑ CYP-450 uses molecular oxygen & inserts one of its oxygen Reactions atoms into a substrate (RH) and reduces the second oxygen to Aromatic/ olefinic. a water molecule utilizing 2 electrons that are provided by Benzylic/ Allylic. NADPH. Aliphatic/Alicyclic C  to C=O Aldehyde/ketone. Aromatization. ❑ Other enzymes responsible for oxidation reactions: Dehalogenation. C  to heteroatom. ▪ Monoamine oxidase. ▪ Alcohol dehydrogenase. ▪ Xanthine oxidase. 34 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation M Arene Epoxide (E+) Toxic ❑ Arene oxide is highly reactive → binds to cellular macromolecules [M] as DNA & proteins → toxicity 35 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Detoxification of Arene oxide NIH Shift OH Phenolic [Arenol] Metabolite Major Epoxide Hydrolase Enzyme OH O Trans Dihydrodiol Metabolite Arene Oxide OH Glutathione-S-Transferase Enzyme SG Glutathione = GSH Glutathione Adduct OH 36 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation EWG Rules: 1. Monosubstituted →Hydroxylation in: a. Para-position. E-Deficient b. Electron-Rich ring. OH EDG E-Rich ❑ Hydroxylation is faster in electron-rich rings [with electron-donating group] → activated rings. 37 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Rapid P-hydroxylation Electron donating group Fast metabolism & have short t 1/2 38 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Rules: 2. Deactivated aromatic rings [with electron-withdrawing group as Cl, NO2, COOH…] → not hydroxylated or slowly hydroxylated. These compounds resist metabolism & have long t 1/2 39 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Rules: 3. If the drug with two aromatic rings → hydroxylation occurs in the OH more electron-rich ring & usually one ring is attacked. OH OH 40 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Rules: 4. If the compound with two identical aromatic rings → oxidation of one ring only. HO HO OH or or OH 41 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Rules: 5. Hydroxylation occurs at ortho- position if para- position is occupied. HO 42 Phase I Oxidation Reactions Aromatic [= Aryl = Arene] Oxidation Rules: Hydroxylation occurs in electron Rich ring and in the p-position If two rings If p-position occupied Different Identical o-hydroxylation The electron rich One ring only ring only 43 Phase I Oxidation Reactions Alkene [Olefinic] Oxidation: Epoxide Hydrolase Enzyme Trans Alkene Epoxide Dihydrodiol Cellular Toxicity O (Major) 44 Phase I Oxidation Reactions Allylic C Oxidation: Allylic C 45 Phase I Oxidation Reactions Benzylic C Oxidation: Benzylic C Primary Alcohol Aldehyde Carboxylic Acid 46 Phase I Oxidation Reactions  C Aliphatic Oxidation: − C ❑  [ultimate or terminal C] &  -1 [penultimate C] oxidation. ❑ This oxidation commonly takes place in drug molecules with straight or branched alkyl chains. ❑ Alcohol metabolites are formed → further oxidation to aldehydes & ketones [Or directly conjugated with glucuronic acid]. 47 Phase I Oxidation Reactions Alicyclic Oxidation: ❑ Hydroxylation of cyclohexyl group occurs at C3 or C4 → cis & trans stereoisomers 48 Phase I Oxidation Reactions Examples Oxidation of C atom - to carbonyl & imine 49 Phase I Oxidation Reactions Aromatic Olefinic Allylic Benzylic Aliphatic Alicyclic Structure Intermediate Epoxide - Product ω-oxidation → 1. Phenol 1ry Alcohol → (Major) Aldehydes or 1ry Alcohol → C 3 or C 4 2. DNA Adduct glucuronidation Trans- Trans- or Cis Aldehyde → → Cis or 3. Trans- dihydrodiol - Alcohol Acid Trans dihydrodiol ω-1-oxidation Conformer 4.Glutathione → 2ry Alcohol conjugate → ketones or glucuronidation THANK YOU You can find me at: ⦿ [email protected] 51