Introduction to drug metabolism - Philadelphia University
Phase-II Drug Metabolism Pharmaceutical Medicinal Chemistry-I Dr. Bilal Al-Jaidi Assistant Professor in Medicinal Chemistry and Drug Design Faculty of Pharmacy, Philadelphia University-Jordan Email: [email protected] Learning Outcomes At the end of this lesson, students will be able to: Define what Phase-II drug metabolism mean. Demonstrate the different routes of Phase-II metabolism in body. Explain the effect of Drug Metabolism on drugs duration of action and activity. Classify mechanisms of drug metabolismPhase-II and enzymes involved. Outline the role of drug metabolism in drug toxicity and carcinogenicity. Phase-II Drug Metabolism Reactions which conjugate the drug or its phase-I
metabolite with a hydrophilic, endogenous species (conjugation reactions). These endogenous compounds are: Glucuronic acid Sulfate group Amino acid (Glycine) Methyl group (as SAM) Acetyl group (as acetyl CoA) Glutathione (tripeptide) NH2 N N SAM O S - OOC Glutathione
N N OH OH NH2 Methyl source Sulfate Glucuronic acid Acetyl CoA Glycine Phase-II Drug Metabolism Involves the following conjugation reactions that are catalyzed by transferase enzymes: Glucuronidation. Sulfation. Amino acid conjugation.
Methylation. Acetylation. Phase-II Drug Metabolism The drug must have a group capable of forming a bond with the endogenous compound. If the drug does not have such group, it will undergo phase-I metabolism, then phase-I metabolite will be conjugated during phase-II reactions. DRUG PHASE-I PHASE-II EXCRETION Phase-II Drug Metabolism Most of the time gives metabolite that is: More polar Non-toxic Pharmacologically inactive
G Endogenous compound Drug XH G Drug X Phase-II drug conjugate Active drug X = O, N, S Phenol, alcohol and carboxylic acid Amine (aliphatic and aromatic) Thiol
Excreted in urine Sometimes: Phase-II gives: Less polar conjugate: Methylated drug Acetylated drug Toxic metabolite: Some sulfate conjugates Some Acetylated metabolites. Glucuronidation Involves conjugation of drug with glucuronic acid. O HO HO HO R D
O OH OH G U IT must be activated to be a good leaving group Glucuronic acid Hydroxyl group is a bad leaving group HO HO HO Glucose-6-phosphate O OH O
OH O P O Uridine triphosphate phosphorylase HO HO HO UDP-Glucose O OH OH OH O O O P P Uridine O O
HO O HO HO OH UDP-Glucose O O OH OH O O P P Uridine O O UDPG-dehydrogenase
HO HO HO O OH UDP-Glucuronic acid O OH OH O O P P Uridine O O Mechanism of conjugation DRUG
O HX HO O HO HO OH O OH OH O O P P Uridine O O OH
O UDP-glucuronosyl transferase OH O O P P O O O HO HO HO O OH
X DRUG Drug-Glucuronide conjugate Uridine Examples Estradiol Examples N HO UDP-glucuronosyl transferase O O OH Morphine N
HO HO HO O O O OH OH Major metabolite Morphine is extensively metabolized into glucuronide conjugate Example of C-glucuronidation N N O H N N
O O O S S O OH Sulfinpyrazone HO HOHO Example of C-glucuronidation O O O Alkaline condition
R R O R R H Nucleophilic carbanion Base O Nucleophilic attack HO Because this H-atom is acidic HO HO
O O O O HO HO HO OH OH O R R O C-Glucuronide OH OH O
O P P Uridine O O Possible groups for glucuronide conjugation Possible groups for glucuronide conjugation Sulfation (sulfate conjugation) Occurs primarily for phenols and occasionally for alcohols, arylamines, and N-hydroxy compounds catalyzed by sulfotransferase enzyme. Sulfotransferase is available mainly in liver, but can be found in kidney, intestine and other tissues Sulfation Also occur for endogenous compounds, such as
steroids, thyroxin, catecholamine and heparin. OH O HO OH OH HO HO O Adrenaline Prednisolone I H2N COOH
O I I HO I Thyroxine H N Sulfation The first step is the bioactivation of inorganic sulfate by enzyme called ATP sulforylase to give the coenzyme 3'-phosphoadosine-5phosphosulfate (PAPS) ATP O O S O O
PPi ATP sulforylase O O O S O P O O OH H2O3PO PAPS O Adenine
OH Sulfation The second step here is the transfer of sulfate group from the coenzyme PABS to the acceptor drug by nucleophilic attack: O ____ DRUG OH O O S O P O
O OH H2O3PO O O Adenine O P O O Adenine OH OH H2O3PO
PAPS PAP O DRUG___ O S O O Drug sulfate conjugate OH As in all conjugation reactions: The endogenous polar group must be activated and converted into electrophilic derivative. Then the drug nucleophilic group will attack the reactive form get the polar, ionizable endogenous molecule. Good Leaving Group Endogenous
molecule Endogenous molecule H Endogenous molecule X DRUG X DRUG Examples of sulfation OH HO HO COOH HO
NH2 HO -methyldopa OH HO OH Terbutaline H N Salbutamol H N Most of the time, sulfate conjugation will give non toxic, polar and easily excreted metabolite. Sometimes, the sulfate conjugate will be converted
into toxic metabolite when the sulfate leaves the compound leaving a highly electrophilic intermediate. O HN OH O HO N OH O HN O O3SO N
OSO3 O-sulfate conjugate Non toxic easily excreted OH O-sulfate conjugate Toxic metabolie O O O3SO N N OH O N-acetyl imidoquinone Microsomal proteins
O HN Hepato and Nephrotoxicity O Microsomal proteins Acetylation Is a reaction of amino groups involving the transfer of acetyl group to: An aromatic or aliphatic primary amine Amino acids Hydrazine Hydrazide Sulfonamides Secondary and tertiary amines are not acetylated. Acetylation The acetylated drug is generally inactive and
noon toxic. In contrast to other metabolic transformations, acetylation ends with less polar metabolite compared to the parent drug In some cases, the acetylated metabolite will be as active as the original drug. Example of active acetylated metabolite O O N H H2N N N H N
HN Procainamide O N-acetylprocainamide pharmacologically active Example of toxic acetylated metabolite H N O O NH2 N H N O
N H O Hydrolysed OH O H2N N H N N N-acetylizoniazid N-oxidation O Liver damage
Proteins Covalent binding O with liver proteins Highly reactive specie Example of toxic acetylated metabolite O O N S N H S O O N S N H O
N H H2N N-acetylsulfathiazole Sulfathiazole Less water soluble than sulfathiazole Precipitate out in the urine Cause crystalluria.kidney failure S Mechanism of acetylation Acetyl CoA is the activated carrier for acetyl group The reaction catalyzed by the soluble acetyltransferase enzyme: Mainly found in liver Might found in lung, spleen, GIT and red blood
cells Mechanism of acetylation O S O N H N O N H H2N O OH O P
HO O O P HO O N N N O OH NH2 Acyl CoA N-acetyltransferase H N O
CoA-SH O3PO Examples of acetylation O H2N H N OH N Histamine P-aminosalicylic acid NH2 N N HN NH2
Hydralazine Acetylation The rate of acetylation is mainly affected by the existence of genetic polymorphism. Two acetylator phenotypes: Slow acetylators: tend to accumulate higher blood concentrations of un-acetylated drugs...toxicity (isoniazid peripheral nerve damage and liver damage) Fast acetylators: eliminate drugs more rapidly, at the same time can form toxic metabolite very fast. Egyptians and western Europeans are slow acetylator Eskimos and Asians are rapid acetylator 1. An introduction to Medicinal Chemistry by Graham L. Patrick. 4th edition, Oxford, 2009 2. Wilson and Gisvolds text book of organic medicinal and pharmaceutical chemistry by John H. Black and John M.
Beale, jr. 12th edition, Lippincott Williams and Wilkings 2011. 3. Foyes principle of medicinal chemistry by David H. Williams, Thomas L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th edition, 2013. The End
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