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Drug Metabolism • Drug Metabolism: The biochemical changes that occur on drugs or other foreign compounds, the purpose of which is to facilitate elimination from the body. Body Drug (lipophilic) Enzyme Metabolite (polar) Excretion • Without it, xenobiotics can remain indefinitely in the body. • It may lead to the formation of inactive and non-toxic compounds, hence the term detoxification. • However, more recent studies have shown that some metabolites are not only active, but may be toxic. Example: OH Metabolism O N A F Haloperidol B Cl BCPP+ 1 Categories of Drug Metabolism Reactions A) Oxidative 1. Phase I Reactions: (Functionalization) B) Reductive C) Hydrolytic - Introduces Polar Functional Groups: e.g. –OH, -COOH, -NH2 2. Phase II Reactions: (Conjugation) Combination-type Reactions Eg, A + B = AB - Attaches Polar and Ionizable Endogenous Groups so as to achieve complete solubility - It also tends to lower or terminate biological activity 2 Phase I Reactions 1) Direct Attachments: OH Aromatic Hydroxylation CH3 OH Aliphatic Hydroxylation CH3 2) Unmask Existing Functional Groups A) Oxidation R R C H2 OH O Oxidation R1 C O Oxidation H R1 C OH O C H2 O CH3 RNHCH2CH3 O-Demethylation N-Deethylation R CH2OH + H C H O R NH2 + H3C C H 3 B) Reduction O R1 C OH Reduction R2 C R1 R2 H R NO2 ; Reduction R NH2 Nitro group Ketone R1 N N R2 Reduction R1NH2 + R2NH2 AZO group C) Hydrolysis O R1 C O R2 O Hydrolysis R1 C + R2 OH OH Ester O R1 C N H R2 O Hydrolysis R1 C + OH R2NH2 Amide 4 Phase II Reactions 1) Glucuronic Acid Conjugation HOOC O R 5 OH + HO H 1 HO 3 Phase I metabolite or parent xenobiotic O OH O UDP-Glucuronyl Transferase HOOC O 5 UDP Actived Uridine-5’-Diphosphoa-D-Glucuronic Acid (Note a-linkage at C-1) HO HO O O R 1 3 OH H b-Glucuronide (Note b-linkage at C-1) 5 2) Sulfate Conjugation OH PAP O + O Phase I metabolite or parent xenobiotic O S O OH S OH Activated 3’-PhosphoAdenosine-5’-Phospho-Sulfate R H N O + PAP O S OH O R NH2 O O O S O OH 3) Amino Acid Conjugation R + OH CH H2 N R2 O R2 O COOH R N H CH COOH Amino Acid 6 4) Other Phase II Reactions Generally, these do not increase water Solubility but mainly terminate activity A) Methylation OH OH HO NH2 O-Methylation H3CO COMT HO NH2 HO Active Inactive B) Acetylation O O NH2 N-Acetylation N H N N H H N CH3 O N Active Inactive Note: Both methylation and acetylation lead to lower solubility and often lead to inactivation 7 Serves as a protective mechanism against electrophilic species C) Glutathione Conjugation (GSH) O + + NH2 HS CH2CH NHCOCH2CH2CHCOOH OH CONHCH2COOH Arene Oxide GSH SG OH SCH2CHNHCOCH3 COOH 8 Sites of Drug Biotransformation • Liver - most important - Most drug metabolizing enzymes - Orally administered drugs first pass through the liver and thus are susceptible to First-Pass Effect. This can lead to lower bioavilability. For example, Lidocaine is inactive when given orally due to the first-pass effect N N a, b NH2 + O Lidocaine (Xylocaine) HO O N H a. Microsomal Oxidation b. Microsomal Amidase • Other Sites: Intestine; Kidneys; Lungs; Skin; Placenta; Brain; Adrenal Glands 9 Oxidative Biotransformations of Drugs - By far the most widespread and the most important - General Reaction: R-H + O2 + H+ NADPH Enzyme R-OH + NADP+ + H2O - Enzyme System: Mixed Function Oxidases or Monooxygenases, the most important component is Cytochrome P-450. - Cytochrome P-450 is responsible for transferring an Oxygen atom to the substrate R-H -NADPH: Reduced Nicotinamide Adenosine Dinucleotide Phosphate. 10 1) Aromatic Hydroxylation O R R Arene OH R Arenol Arene Oxide • Hydroxylation often occurs para to the substituent on the ring • Occurs on the more activated ring, common activating groups: -OH; -OCH3; -NH2; -NHR; and Alkyl group, e.g. -CH3, -CH2CH3, etc • Deactivated rings are resistant to oxidation, common deactivating groups: -F, -Cl, -Br, -NO2, -SO2NHR, -COR etc Example: O OH N H Propranolol (Inderal®) O OH N H OH 11 2) Olefinic Oxidation -Oxidation of olefinic “C=C” double bond leads to epoxide e.g. HO O N O N N NH2 O Carbamazepine (Anticonvulsant) OH O NH2 Epoxide NH2 Trans-diol 3) Benzylic Carbon Oxidation e.g. 1 O O O SO2NHCNHC4H9 SO2NHCNHC4H9 SO2NHCNHC4H9 CH2 CH3 Tolbutamide (Orinase) Hypoglycemic Agent CH2OH Alcohol Metabolite COOH Carboxylic Acid Benzylic Carbon 12 OH OH OCHCHCH2NHCH(CH3)2 e.g. 2 OCHCHCH2NHCH(CH3)2 Metoprolol (Lopressor) (b-Adrenergic Blocker) CH2CH2OCH3 HO CHCH2OCH3 4) Allylic Carbon Oxidation H2C C H CH2 Allylic Carbon e.g. 7 7 1 6 7 7 HO 2 6 3 5 OH 3 + 6 3 + HO 6 3 4 O C5H11 Tetrahydrocannabinol (D1-THC) (Hallucingen) 7-Hydro- D1-THC 6b6a(equal or more active) (minor) (minor) No 3-metabolite due to steric hindrance 13 5) Oxidation of Carbon Atom a to C=O or C=N O N Cl N Diazepam O N H OH N Cl Hydroxydiazepam 6) Alicyclic and Aliphatic Carbon Oxidation A) Oxidation at a Terminal Carbon (w-Oxidation) B) Oxidation at Penultimate Carbon (w-1-Oxidation) e.g. HOOC C3H7 C3H7 A OH CH2CH2CHCOOH Valproic Acid CH2CH2CH2CHCOOH (Antiepileptic Agent) C3H7 C3H7 B CH3CHCH2CHCOOH CH3CH2CH2CHCOOH OH 14 C) Alicyclic Hydroxylation O O e.g. Acetohexamide (Dymelor) O O S NH O N H 4 O O S NH O N H H H H 4 OH H H trans-4-OH- 7) Oxidation Involving Carbon-Heteroatoms (Also cis-4-, trans-3- , cis-3- as minor) A) Oxidative N-Dealkylation e.g. CH3 N H3C CH3 HN C H2 C H2 CH3 NH2 Benzphetamine Note: - Small alkyl group is preferentially removed - First alkyl group is removed at faster rate than the second one 15 B) Direct Oxidation on N-Atoms O O e.g. O O N-Oxidation N N H3C CH3 O Meperidine-N-Oxide Meperidine C) Oxidative Deamination e.g. 1 H H aC O NH2 a-Carbon CH3 Hydroxylation C CH3 NH2 -NH3 C O CH3 Amphetamine Note: For endogenous amines i.e. Dopamine, Norepinephrine, Serotonin etc. the group of enzymes responsible for deamination is called Monoamine Oxidase (MAO) 16 e.g. 2 HO MAO NH2 HO HO C HO O H Dopamine D) O-Dealkylation e.g. NHCOCH3 NHCOCH3 NHCOCH3 O + O CH2CH3 O CHCH3 O Phenacetin H CH3CH OH Acetaminophen (Tylenol) 17 E) S-Dealkylation e.g. SCH3 SH N N N H N 6-(Methythio)Purine N N N N H 6-Mercaptopurine F) Desulfuration e.g. O HN S N H O CH2CH3 O CHCH2CH2CH3 CH3 Thiopental CH2CH3 HN O N H O CHCH2CH2CH3 CH3 Pentobarbital 18 G) Direct Oxidation of Sulfur e.g. S S N S CH3 H2CH2C N N S H2CH2C O CH3 N CH3 CH3 Thioridazine (Mellaril) Mesoridazine (Serentil) Active O S O N H2CH2C S CH3 S O S O Sulfoxide Sulfone N CH3 Sulfoxide drugs and metabolites may be further oxidized to sulfones 19 H. Oxidation of Alcohols and Aldehydes O Alcohol R CH2OH Dehydrogenases R C O Aldehyde H Oxidase R C OH 8) Other Oxidations A) Aromatization Et HO C CH O Norgestrel (Oral Contra) Et HO C CH HO 17a-Ethinyl-18-Homoestradiol (Minor Metabolite in Women) 20 B) Dehalogenation H H Cl C Cl Cl Chloroform O Cl C Cl H2CO3 + HCl -HCl O Cl + H2O C Cl Cl Tissue Nucleophies Covalent Binding Phosgene 21 Question Predict the metabolic products of the following compounds: (1) S N Cl CH2CH2CH2 N H3C CH2CH3 (2) CH3 CH2OCH2CH2 N C CH3 H CH3 22 Reductive Biotransformations - Carbonyl (C=O), Nitro (NO2), and Azo (N=N) groups susceptible to reduction 1) Reduction of C=O e.g. O O H H N C N S O C CH3 Aldo-Keto Reductases (NADPH) O Acetohexamide O O H H N C N S O C CH3 HO H S(-) Hydroxyhexamide (Note asymmetric center is introduced) 23 2) Reduction of NO2 group e.g. O O2N O C N N H NH O Dantrolene Nitro Reductase O H2N O H2N S O H2N N N Sulfamidochrysoidine (Prontosil) NH O Aminodantrolene 3) Reduction of AZO group O H2N S O O C N N H NH2 + NH2 Sulfanilamide (Active) H2N H2N NH2 24 Hydrolytic Reactions 1) Hydrolysis of Esters e.g.1 COOH O COOH CH3 Esterases O Aspirin O OH + HO CH3 Salicylic Acid e.g.2 Cl O O Cl O EtO Clofibrate (Atromid-S) Hypolipidemic Drug O HO Active 25 Note: Formation of active drugs from deliberately masked drugs is the basis of the Prodrug concept: e.g.1 Chloramphenicol is too bitter to use orally. The Palmitate ester is made to mask bitterness: O OH NHCCHCl2 O2N O C CH2CH2 O C (CH2)14CH3 H e.g.2 Carbenicillin has poor oral absorption, the Indanyl ester is made to increase absorption: O C6H5 O O C CH C HN N O COOH 26 2) Hydrolysis of Amides - Amides are more slowly hydrolyzed than esters. H3CO H3CO O N N N C N NH2 Prazosin (Minipress) Selective a-1 Blocker H3CO N O N NH N H3CO NH2 + O HO C O 27 Phase II Conjugation Reactions - The following groups are involved: COOH O OH O HO S OO OH Sulfate CH3 Methyl HS O UDP OH Glycine COOH O O a-Glucuronic Acid H2N C COOH H2 NH2 H N N H COOH Glutathione NH2 O H2N C CH2CH2CH COOH Glutamine O C CH3 Acetyl - These groups are transferred by the appropriate conjugation enzymes on to the drugs or other metabolites 28 - The following functional groups are susceptible to conjugation: OH O R C OH RCH2OH R NHCOR2 RNH2 R1 R SO2NHR2 RSH R N R2 R X H R CH R2 1) Glucuronic Acid Conjugation -The most common conjugative pathway - Steps: a. Synthesis of activated glucuronic acid (UDPGA) b. Enzymatic transfer COOH O OH OH + O UDP OH COOH O OH R X H OH XR OH UDPGA (Uridine-5’-DiPhospho-a-D-Glucuronic Acid) 29 A) O-Glucuronides e.g.1 O HN C CH3 OH + UDPGA COOH O OH OH O NH C O OH Acetaminophen e.g.2 O OH O C OH + UDPGA COOH O OH OH O OH C OH Salicylic Acid 30 B) N-Glucuronides + UDPGA N (CH2)3 NHCH3 N COOH O OH OH N (CH2)3 CH3 OH C) S-Glucuronides N N CH3 N SH + UDPGA COOH O OH OH S N CH3 OH 31 - Glucuronic acid conjugates are excreted mainly through urine. If molecular mass exceeds 300 DA, biliary route becomes important. Enterohepatic Circling (Reflux): 1. Drug undergoes glucuronidation in the liver 2. Glucuronide excreted in the bile 3. Hydrolyzed by b-Glucuronidases in intestine 4. Hydrolyzed drug reabsorbed in intestine LIVER Drugs or endogenous compounds Glucuronide Absorption Excretion Hydrolyzed Drug b-Glucuronidases INTESTINE 32 2) Sulfate Conjugation - Occurs primarily in phenols, but possible in aromatic amines, alcohols H and N-hydroxy compounds R N OH - Mechanism of Transfer: 1. Activation of Sulfate (SO42-) to PAPS 2. Transfer of SO42- from PAPS to substrate (drug) O O O P O S O OH 5' O Adenine O HO N H + C(CH3)3 HOH2C OH 3’-Phosphoadenosine-5’phosphosulfate (PAPS) N H -PAP 1' 3' H2O3PO C(CH3)3 HO HOH2C OH O O S OH O Sulbutamol (b-Adrenergic Bronchodilator) 33 3) Conjugation with Amino Acids and Glutathione A) Conjugation with Glycine and Glutamine - Glycine and Glutamine are used by mammalians to conjugate –COOH, especially aromatic acids and arylalkyl acids - Mechanism of transfer: a. Substrate (carbonic acid) is activated with ATP Coenzyme A to form acyl-CoA complex. b. Then the acyl-CoA complex acylates glycine or glutamine with specificN-acyltransferase. CoAS OH O ATP CoA O NH2 RH C HOOC NH RCHCOOH O N-acyltransferase 34 e.g. OH O C(CH2)3 N Cl F Haloperidol p-Flourophenylacetic Glycine Conjugate Acid B) Conjugation with Glutathione - Important to detoxify reactive electrophilic species, which may otherwise form covalent bond with nucleophilic groups in proteins and nucleic acids - Catalyzed by cytoplasmic enzymes known as glutathione S-transferases - Do not require coenzyme to activate substrate. - Electrophilic species: 1) electron-deficient carbon or heteroatom 2) electron-deficient double bond GSH H2C R - X GS CH2 + HX R 35 O + H N HS COOH N H COOH Glutathione S-Transferase NH CH3 S O O N H OH Mercapturic Acid Der COOH - glutamyl transpeptidase OH OH S O COOH O NH2 OH S Glutathione (GSH) N-Acetylase NH2 H N O O Arene Oxide OH NH2 O OH Cysteinyl Glycinase NH2 S O N H COOH Notice the Glutathione adduct undergoes further Biotransformation: cleavage of glutamic acid and glycine; then N-acetylation 36 4) Other Phase II Biotransformation A) Acetylation H2N O S O Dapsone Antileprotic Agent O NH2 CH3CCoA H2N Acetyltransferases O S O NHC CH3 O Acetylation Polymorphism: - Caused by differences in N-acetyltransferase activity - Rapid Acetylators = Eskimos & Orientals-R - Slow Acetylators = Egyptians & W. Europe-S Consequences: - Rapid Acetylators -- often show inadequate therapeutic response -Slow Acetylators -- may show adverse drug reaction but greater therapeutic response 37 B) Methylation - Like acetylation, leads to lower solubility - Primary function is attenuation of activity - Constitutes only a minor pathway - Coenzyme: S-Adenosylmethionine (SAM) HOOC H CH3 NH2 C CH2CH2 S CH2 Adenine O SAM HO OH - Compounds which undergo methylation reaction: OH OH R1 R OH N R R2 SH N - Enzymes involved: Catechol-O-methyltransferase (COMT); Phenol-O-methyltransferase; Other non-specific N- and S-methyltransferase 38 Examples of Methylation Reactions: i) O-methylation HO 3 H2 C H3CO CH3 C COOH NH2 H2 C COMT CH3 C COOH NH2 HO HO S(-)-a-Methyldopa - antihypertensive - only position 3 is methylated, and bismethylation does not occur - COMT metabolizes only catechols Question: Is terbutaline (Brethine) a substrate for COMT? OH HO CH NHC(CH3)3 C H2 OH 39 ii) N-methylation OH OH CH CH NH2 CH CH CH3 CH3 N N N H3C N H3C CH3 iii) S-methylation SH N C3H7 NHCH3 SCH3 N N OH C3H7 N OH 40 Factors Affecting Drug Metabolism 1. Age; 2. Species/Strain; 3. Hereditary; 4. Sex. Assignment: Read “Wilson & Gisvold,” Chapter on Metabolism Effect of Other Xenobiotics A) Enzyme induction: When a drug causes an increase in the activity of an enzyme, often due to increased amounts of newly synthesized enzymes this would result in: -Result: increase in drug metabolism & decrease rate of drug action, therefore the concomitant use of 2 drugs must be analyzed for drug interaction. - Examples: 1. Phenobarbital is used in the treatment of hyperbilirubinemia because it induces glucuronyltranferase -- the enzyme responsible for glucuronidation of bilirubin. 41 2. Benzo[ a ]-Pyrene (found in cigarette smoke) induces Cyt P-450 and may be responsible for increased rate of metabolism of theophylline in smokers. T 1/2 in smokers = 4.1 h non smokers =7.2 h Assignment: make a table of drugs that induce the metabolism of other drugs. B) Enzyme Inhibition: When xenobiotics cause a decrease in the activity of a drug metabolizing enzyme, - often due to the following: * Substrate competition * Interference with protein synthesis * Inactivation of metabolizing enzymes * Hepatotoxicity - Result: Increase duration of action of drug possible adverse effects. - Examples: 1) Phenylbutazone inhibits S(-)-Warfarin, Tolbutamide 2) Isoniazid `` Phenytoin (Dilantin) 3) Chloramphenicol `` Tolbutamide 42 - General inhibitors of microsomal enzymes: SK & F -525 A, Metyrapone, Peperonyl butoxide, Cobaltous chloride Other Factors A) Diet B) Pathologic state of liver C) Pregnancy D) Hormonal disturbances. Relevance of Drug Metabolism 1. Bioavailability therefore dosage 2. Active and inactive metabolites 3. Metabolite may be toxic 4. Design of new drugs 5. Provide information on organs involved 6. Drug interactions, e.g. enzyme induction, inhibition. 43