Drug Metabolism (Metabolism 2025 Part 1)

Drug Metabolism Biotransformation of foreign compounds (Xenobiotics) by enzyme system in all the body cells and blood (occur specially in the liver) into water soluble derivatives which can be easily eliminated via renal route Movement of Drugs in the Body...

Drug Metabolism Biotransformation of foreign compounds (Xenobiotics) by enzyme system in all the body cells and blood (occur specially in the liver) into water soluble derivatives which can be easily eliminated via renal route Movement of Drugs in the Body Site of Action Absorption Drug in Blood Metabolism Toxicity Tissues Bound Drug in Blood Excretion 1 Pharmacodynamic consequences of metabolism 1. Both are devoid of biological effects. 2. Only xenobiotic elicits biological effects; a situation which in medicinal chemistry is typical of, but not unique to, soft drugs. 3. Both are biologically active; the two activities are comparable or different either qualitatively or quantitatively. 4. The observed biological activity is caused exclusively by the metabolite; (prodrugs). 2  Biological Role of Drug Metabolism 1. Decreasing biological activity of drugs and xenobiotics. 2. Increasing excretion, by conversion to water-soluble metabolites. 3. Bioactivation of prodrugs. Also converts active drugs to different active ones. 4. Generation of toxic or carcinogenic metabolites. 3  Pharmacological Inactivation of Drugs Oxidative Amphetamine CH2-CH-NH2 CH2-C-=O Deamination CH3 CH3 HO O O Phenobarbital NH NH Aromatic Hydroxylation O N O O N O H H O S S Chlorpromazine S-Oxidation N Cl N Cl N N 4  Drug toxification S O Phosphothionate O2N O P OCH2CH3 O2N O P OCH2CH3 oxidation OCH2CH3 OCH2CH3 Parathion Paraoxon Metabolic reactions result in conversion of active drugs to other active ones HN NH2 HN N N-dealkylation N N O O Ipronazid Isoniazid (Antidepressant) (Antituberculosis) Drug Metabolism Results in Pharmacological Activation Alcohol dehydrogenase CCl3CHO.H2O CCl3CH2OH Sedative & hypnotic Chloralhydrate Trichloroethanol (Initial effect) (Prolonged effect) O O NH NH Antiepileptic O O N O N H H Primidone Phenobarbital 6  Pro-drug Conversion Prontosil Sulfanilamide: Antibacterial, competes with p-aminobenzoic acid for conversion to folic acid 7  Non metabolic drugs (hard drugs) Metabolically stable drugs  Highly hydrophilic: Saccharine, enalaprilate, lisinopril and cromolyn.  Highly lipophilic: Polyhalogenated compds e.g. some insectisides.  Can not penetrate and contact with enzymes.  Sterically shielded from metabolic attack. Soft drugs Can be defined as drugs that undergo a predictable in vivo metabolism to form non toxic products after they exert their therapeutic purpose. 8  Bioavailability of drugs  Bioavailability of a drug is defined as the fraction of the dose of a drug that is found in general circulation.  It is influenced by such factors as ADME.  Bioavailability of a given drug is not constant but varies with the body’s physiological conditions. 9 Drug Metabolism Phases 10  Reactions are classed as phase I or phase II Phase I Phase II Oxidation Glucuronidation Reduction Sulfation Hydrolysis Acetylation Hydration Methylation Isomerization Glutathione conjugation Amino acid conjugation Fatty acid conjugation  Phase I metabolism I- Oxidation 1. Cytochromes p450 (major) 2. Flavin-containing monooxygenases 3. Xanthine oxidase Enzymes 4. Epoxide hydrolase involved in phase I Examples of Reactions Catalyzed by Cytochromes P450 Aromatic hydroxylation Aliphatic hydroxylation Epoxidation N-Dealkylation O-Dealkylation S-Dealkylation Oxidative Deamination N-Oxidation S-Oxidation Phosphothionate oxidation Oxidative dehalogenation Alcohol oxidation  Phase I metabolism Cytochromes P450  Cytochrome P450 are mixed function oxidases (MFO) which activate molecular oxygen to insert one oxygen atom into a variety of lipophilic substrates and the other one being reduced to water  Haemoprotein cytochrome P-450: The terminal oxidase enzyme localized to endoplasmic reticulum of liver cells , which catalyzes the oxidative metabolism of a wide variety of substrates.  P450 isozymes are derived from liver and adrenal mitochondria.  They are primarily found in liver cells, but are also located in cells throughout the body.  These systems catalyze series of oxidative and reductive steps, each step being catalyzed by a specific enzyme. 13  Phase I metabolism  The overall scheme for these reactions is the insertion of a single oxygen atom into the drug molecule. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co- enzymes.  Functional polymorphism has been discovered for several CYP450s (CYP2A6, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5). (the variant of a given gene)  Phase I metabolism Cytochromes P450 Percentage of all prescription drugs metabolized in human liver by a particular CYP enzyme  Phase I metabolism Cytochromes P450  The haem-containing component, with iron protoporphyrin IX1 as the prosthetic group, is the substrate and oxygen-binding site of the enzyme system, whereas the reductase serves as an electron carrier.  Phase I metabolism Cytochromes P450 Structure of Ferric Protoporphyrin IX (Heme) Ferric ion (Fe3+) can form 6 coordinate bonds 4 with nitrogens in porphyrin ring 1 with cysteine in cyp450 protein 1 with substrate 18  I- CYP450 Oxidation Reactions A- Hydroxylation n-C3H7 a) Hydroxylation of saturated aliphatic C atoms (exposed carbon atom) HOH2C COOH ω-oxidn n-C3H7 COOH OH n-C3H7 Valproic acid ω-1 oxidn COOH O O NH NH O O NH NH O O  oxidation Secobarbital  oxidation 19  I- CYP450 Oxidation Reactions A- Hydroxylation b) Aliphatic ring hydroxylation (exposed carbon atom) OH OH O O OH Testosterone Testosterone CH3 CH3 O O SO2 SO2 HN HN O N O N OH H H Acetohexamide 20  I- CYP450 Oxidation Reactions A- Hydroxylation OH c) Hydroxylation at activated SP3 C atoms OH R R OH R R OH R R 1-Ethers X X X = O, NH, S Phenacetin NHCOCH3 NHCOCH3 NHCOCH3 -CH3CHO oxid. dealkylation O O OH OH 21  I- CYP450 Oxidation Reactions A- Hydroxylation N N 2-Amines CH3 Oxid. -HCHO N N CH2OH H dealkylation N CH3 N Br CH3 Bromopheniramine CH3 Br Br oxid. -HCHO dealkylation N N COOH Oxid. Oxidative N O Deamination Br Br NH2 Br H OH + NH3 NH2 NH2 O Amphetamine 22  I- CYP450 Oxidation Reactions A- Hydroxylation 3-Halogenated aliphatic derivatives Cl Cl Cl oxid. Cl OH -HCl H 2O Cl H O CO2 + HCl Cl Cl Cl Hepatotoxic and nephrotoxic effect Phosgene OH Cl OH Cl H H H OH N N Cl Cl O O O2N HO O2N HO Chloramphenicol OH Cl H N -HCl O Toxic effect O O2N HO Oxamyl chloride derivatives 23  I- CYP450 Oxidation Reactions A- Hydroxylation d) Oxidation of unsaturated aliphatic systems SG OH O GSH Major O OH OH Styrene reactive styrene (Epoxide) RS HN SG O Minor Mercapturic acid derivatives Covalent binding to protein Glutathione derivatives 24  I- CYP450 Oxidation Reactions A- Hydroxylation OH O HO HO OH Diethylstilbestrol O O OH HO HO HO O- * H C D D C D * α- Ethynyl steroid Oxirene Ring exapansion 25  I- CYP450 Oxidation Reactions A- Hydroxylation e) Hydroxylation of aromatic rings M = Macromolecules, protein, DNA, …. 26  I- CYP450 Oxidation Reactions A- Hydroxylation E.g.: Metabolism of benzen OH + + H H OH O OH OH OH OH E.g.: p-Hydroxylation of nitrobenzene as a major metabolite. 27  I- CYP450 Oxidation Reactions A- Hydroxylation O Benzo[a]pyrene Benzo[a]pyrene-4,5-epoxide 28  I- CYP450 Oxidation Reactions B- N-Oxidation Catalyzed by Cyt-P450 and/or monooxygenase enzyme 1) 3ry amines 2) 1ry and 2ry amines 3) amides 1) 3ry amines N N N N O O N N N N O O 29  I- CYP450 Oxidation Reactions B- N-Oxidation 2- 1ry and 2ry amines →Methemoglobin Deceased oxygen binding capacity 3-Amides 30  I- CYP450 Oxidation Reactions B- N-Oxidation 1ry Amines may also be oxidized into nitroso componds 1,4-Dihydropyridines (as nifidipine) are oxidized and aromitized to pyrimidine derivatives Hydrazines are oxidized to azo compounds, some of which can be oxygenated to azoxy compounds 31  I- CYP450 Oxidation Reactions C- S-Oxidation S containing drugs exist in three forms, thiols (RSH), thioethers (RSR`), and thiocarbonyls RR’C=S. Metabolism of thioles Metabolism of thioethers Metabolism of thiocarbonyls Desulfurization 32  I- CYP450 Oxidation Reactions C- S-Oxidation O O O O E.g. 1: Metabolism of oxisuran S O S (immunosuppressive). CH3 CH3 N Oxisuran N E.g. 2: Metabolism of thioridazine (antipsychotic) O O O S S S N SCH3 N SCH3 CH3 N S R R Sulfone derivative Sulfoxide derivative S S CH3 N CH3 CH3 N S N S O Mesoridazine R O Thioridazine R O Sulforidazine 33  I- CYP450 Oxidation Reactions C- S-Oxidation E.g. 3: Metabolism of thiopental (S-H) CH3 O CH3 O H3C H3C H3C NH oxidative desulfuration H3C NH O N S O N O H H Thiopental Pentobarbital Multiple Phase I Metabolic Pathways for Chlopromazine Sulfur oxidation Ring hydroxylation S Ring hydroxylation N Cl N N-Demethylation N-Oxidation N-Oxidation 34  Ethanol Oxidation to Acetic Acid OH Microsomes CH CH 3 OH CYP2E1 H2O Mitochondria Alcohol Dehydrogenase O ALDH O CH3CH2OH CH3C CH3C Cytosol H OH Ethanol Acetaldehyde Acetic acid NAD+ NADH + H+ NAD+ NADH + H+ Catalase Peroxisomes H2O2 H2O 35  NH CH3 OH N NH CH3 N Cl N O Multiple Phase I Metabolic Cl N O pathway for some OH Benzodiazepenes (BZPs) inactive metabolites inactive metabolites C9 hydroxylation 4 ' hydroxylation : inactive NH CH3 NH2 H O N N N N-dealkylation oxidative deamination Cl Cl N Cl N N O O O Demoxepam Chlordiazepoxide Reduction H3C H O H O O N N N glucouronide conjugation 3-hydroxylation N-dealkylation excretion OH Phase II Cl Cl Cl N N N N-dealkylation Oxazepam ( Nordazepam) Diazepam 36  Dehalogenation Reactions Catalyzed by Cytochrome P450 H OH O H2O O -HBr F3C Br F3C Br F3C F3C -HCl Cl Cl OH Cl Halothane Protein binding Aplastic Anemia 37