DRUG METABOLISM.

DRUG METABOLISM

Introductory Concepts
Biochemically speaking: Metabolism means Catabolism (breaking down of substances) + Anabolism (building up or synthesis of substances) But when we speak about drug metabolism, it is only catabolism i.e drug metabolism is the break down of drug molecules Metabolism plays a central role in elimination of drugs and other foreign compounds from the body. Lipid soluble drugs are not excreted satisfactorily in the urine, so the process of metabolism makes them polar, ionizable and easily excretable which involve both phase I and phase II mechanisms.

What Roles are Played by Drug Metabolism?
One of four pharmacokinetic parameters, i.e., absorption, distribution, metabolism and excretion (ADME) Elimination of Drugs: Metabolism and excretion together are elimination Excretion physically removes drugs from the body The major excretory organ is the kidney. The kidney is very good at excreting polar and ionized drugs without any major metabolism. The kidney is unable to excrete drugs with high lipid solubility In general, by metabolism drugs become more polar, ionizable and thus more water soluble to enhance elimination It also effect deactivation and thus detoxification. Many drugs are metabolically activated (Prodrugs). Sometimes drugs become more toxic and carcinogenic.

Classification of metabolites:
Inactive metabolites Metabolites retain similar activity Metabolites with different activity Bioactivated metabolites (prodrug technique)

Metabolite activity Examples and notes Inactive (detoxification)
Similar activity to the drug Different activity Toxic metabolites Routes that result in the formation of inactive metabolites are often referred to as detoxification. The metabolite may exhibit either a different potency or duration of action or both to the original drug.

Classification of drug metabolic pathways
Drug metabolism reactions have been divided into two classes: Phase I reaction (functionalization) Phase II reaction (conjugation)

Phase I reaction (functionalization)
Purpose of these reactions is to introduce a polar functional group like –OH, -COOH, -SH, NH2by: Direct introduction of the functional group eg. Aromatic & aliphatic hydroxylation. Modifying or unmasking existing fuctional groups eg. Reduction of ketones and aldehydes to alcohol, oxidation of alcohols to acids, hydrolysis of esters and amides.

Classification of Phase –I reactions
1. Oxidation Aromatic moieties Olefins Benzylic & allylic C atoms and a-C of C=O and C=N At aliphatic and alicyclic C C-Heteroatom system C-N (N-dealkylation, N-oxide formation, N-hydroxylation) C-O (O-dealkylation) C-S (S-dealkylation, S-oxidation, desulfuration) Oxidation of alcohols and aldehydes Miscellaneous 3. Hydrolytic Reactions Esters and amides Epoxides and arene oxides by epoxide hydrase Phase II - Conjugation Phase I - Functionalization Drug Metabolism 2. Reduction Aldehydes and ketones Nitro and azo Miscellaneous

Phase II reaction (Conjugation)
Purpose of these reactions is to attached a polar and ionizable endogenous compounds such as glucoronic acid, sulfate, glycine and other amino acids to the functional handles of phase I metabolites or parent compound. These conjugated metabolites are readily excreted in the urine and are generally devoid of pharmacological activity.

Classification of Phase II reaction (Conjugation)
Glucuronic acid conjugation Sulfate Conjugation Glycine and other AA Glutathion or mercapturic acid Acetylation Methylation Phase I - Functionalization Phase II - Conjugation Drug Metabolism

General Metabolic Pathways
Oxidation Aromatic moieties Olefins Benzylic & allylic C atoms and a-C of C=O and C=N At aliphatic and alicyclic C C-Heteroatom system C-N (N-dealkylation, N-oxide formation, N-hydroxylation) C-O (O-dealkylation) C-S (S-dealkylation, S-oxidation, desulfuration) Oxidation of alcohols and aldehydes Miscellaneous Hydrolytic Reactions Esters and amides Epoxides and arene oxides by epoxide hydrase Phase II - Conjugation Phase I - Functionalization Drug Metabolism Reduction Aldehydes and ketones Nitro and azo Miscellaneous Glucuronic acid conjugation Sulfate Conjugation Glycine and other AA Glutathion or mercapturic acid Acetylation Methylation

Sites of Drug Metabolism
Liver: Major site, well organized with all enzyme systems Intestinal Mucosa: The extra-hepatic metabolism, contains CYP3A4 isozyme Isoproterenol exhibit considerable sulphate conjugation in GI tract Levodopa, chlorpromazine and diethylstilbestrol are also reportedly metabolized in GI tract Esterases and lipases present in the intestine may be particularly important carrying out hydrolysis of many ester prodrugs Bacterial flora present in the intestine and colon reduce many azo and nitro drugs (e.g., sulfasalazine) Intestinal b-glucuronidase can hydrolyze glucuronide conjugates excreted in the bile, thereby liberating the free drug or its metabolite for possible reabsorption (enterohepatic circulation or recycling)

Enzymes Involved in Drug Metabolism
CYP450 :- Carry out oxidation reactions Hepatic Microsomal Flavin Containing Monooxygenases (MFMO or FMO):-Oxidize S and N functional groups Monoamine Oxidase (MAO): carry out Non-Microsomal Oxidation Reactions Hydrolases:- Oxidize S and N functional groups

Enzymes Involved in Drug Metabolism
CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO or FMO) Monoamine Oxidase (MAO) and Hydrolases Cytochrome P450 system: localized in the smooth endoplasmic reticulum. Cytochrome P450 is a Pigment that, with CO bound to the reduced form, absorbs maximally at 450nm Cytochromes are hemoproteins (heme-thiolate) that function to pass electrons by reversibly changing the oxidation state of the Fe in heme between the 2+ and 3+ state and serves as an electron acceptor–donor It catalyzes various Oxidation reactions by activating molecular oxygen and causese oxidation of diverse substrates(Drugs) by variety of oxiation reactions. Simplified apoprotein portion Heme portion with activated Oxygen

Oxidative Reactions catalysed by CYP450.

oxidation Reactions:-

Various types of oxidation reactions:-
Aromatic Hydroxylation Olefins Benzylic & allylic C atoms and a-C of C=O and C=N At aliphatic and alicyclic Carbon atom C-Heteroatom system 1.C-N (N-dealkylation, N-oxide formation, N-hydroxylation) 2.C-O (O-dealkylation) 3.C-S (S-dealkylation, S-oxidation, desulfuration) Oxidation of alcohols and aldehydes Miscellaneous

1.Aromatic Hydroxylation
Hydroxylation is the primary reaction mediated by CYP450 Hydroxylation can be followed by non-CYP450 reactions including conjugation or oxidation to ketones or aldehydes, with aldehydes getting further oxidized to acids Hydroxylation of the carbon α to heteroatoms often lead to cleavage of the carbon – heteroatom bond; seen especially with N, O and S, results in N–, S– or O–dealkylation. Must have an available hydrogen on atom that gets hydroxylated, this is important!!! Aromatic Hydroxylation

Aromatic Hydroxylation
OH Epoxide Hydrase Mixed function oxidation of arenes to arenols via an epoxide intermediate arene oxide Major route of metabolism for drugs with phenyl ring Occurs primarily at para position Substituents attached to aromatic ring influence the hydroxylation Activated rings (with electron-rich substituents) are more susceptible while deactivated (with electron withdrawing groups, e.g., Cl, N+R3, COOH, SO2NHR) are generally slow or resistant to hydroxylation

Amphetamine Phenytoin p-hydroxyphenytoin Warfarin sodium Propranolol Phenylbutazone Atorvastatin

Preferentially the more electron rich ring is hydroxylated
Antihypertensive drug clonidine undergo little aromatic hydroxylation and the uricosuric agent probenecid has not been reported to undergo any aromatic hydroxylation Probenecid Clonidine Preferentially the more electron rich ring is hydroxylated Diazepam Chlorpromazine NIH Shift: Novel Intramolecular Hydride shift named after National Institute of Health where the process was discovered. This is most important detoxification reaction for arene oxides

2.Oxidation of olefinic bonds (also called alkenes)
The second step may not occur if the epoxide is stable, usually it is more stable than arene oxide May be spontaneous and result in alkylation of endogenous molecules Susceptable to enzymatic hydration by epoxide hydrolase to form trans-1,2-dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds)

Protriptyline Cyproheptadine
2.Oxidation of olefinic bonds (also called alkenes) Protriptyline Cyproheptadine

3.Benzylic Carbon Hydroxylation
Hydroxylate a carbon attached to a phenol group (aromatic ring) R1 and R2 can produce steric hindrance as they get larger and more branched So a methyl group is most likely to hydroxylate Primary alcohol metabolites are often oxidized further to aldehyde and carboxylic acids and secondary alcohols are converted to ketones by soluble alcohol and aldehyde dehydrogenase Tolbutamide Metabolism Tolmetin sodium Dicarboxylic acid is the major metabolite

3.Benzylic Carbon Hydroxylation
Imipramine Amitriptyline

4.Oxidation at Allylic Carbon Atoms
The allylic C is the C atom next to double bond. Eg. Tetrahydrocarnnabinol- it have three allylic centers C3, C6 and C7 but hydroxylation will take place Preferentially at C7.

4.Oxidation at Allylic Carbon Atoms
Pentazocine

5.Hydroxylation at a Carbon to C=O and C=N
The benzodiazepines are classic examples with both functionalities The sedative hypnotic glutethimide possesses C a to carbonyl function

6.Aliphatic Carbon hydroxylation
Catalyzes hydroxylation of the ω(terminal C) and ω-1 carbons in aliphatic chains Generally need three or more unbranched carbons . Alcohol metabolite is formed which further gives aldehyde, ketone or acid Pentobarbital Metabolism ω-1 + Ibuprofen Metabolism ω ω hydroxylation hydroxylation

6.Alicyclic (nonaromatic ring) Hydroxylation
Cyclohexyl group is commonly present in many drug molecules The mixed function oxydase tend to hydroxylate at the 3 or 4 position of the ring Due to steric factors if position 4 is substituted it is harder to hydroxylate the molecules Acetohexamide Metabolism

7. Oxidation Involving Carbon-Heteroatom(C-X) Systems
It includes three types of C-X systems:- C-N, C-O C-S (occasionally)

7. Oxidation Involving Carbon-Heteroatom(C-X) Systems
C-N, C-O and occasionally C-S Two basic types of biotransformation processes: Hydroxylation of a-C attached directly to the heteroatom (N,O,S). The resulting intermediate is often unstable and decomposes with the cleavage of the C-X bond: Oxidative N-, O-, and S-dealkylation as well as oxidative deamination reaction fall under this category Hydroxylation or oxidation of heteroatom (N, S only, e.g., N-hydroxylation, N-oxide formation, sulfoxide and sulfone formation) Metabolism of some N containing compounds are complicated by the fact that C or N hydroxylated products may undergo secondary reactions to form other, more complex metabolic products (e.g., oxime, nitrone, nitroso, imino)

A. C-N systems Aliphatic (1o, 2o, 3o,) and alicyclic (2o and 3o) amines; Aromatic and heterocyclic nitrogen compounds; Amides Enzyme 3o Aliphatic and alicyclic amines are metabolized by oxidative N-dealkylation (CYP) Aliphatic 1o, 2o amines are susceptible to oxidative deamination, N-dealkylation and N-oxidation reactions Aromatic amines undergoes similar group of reactions as aliphatic amines, i.e., both N-dealkylation and N-oxidation

N-Dealkylation (Deamination)
Deamination and N-dealkylation differ only in the point of reference; If the drug is R1 or R2 then it is a deamination reaction and If the drug is R3 or R4 then it is an N-dealkylation In general, least sterically hindered carbon (a) will be hydroxylated first, then the next, etc. Thus the more substituent on this C, the slower it proceeds; branching on the adjacent carbon slows it down, i.e. R1, R2 = H is fastest. Any group containing an a-H may be removed, e.g., allyl, benzyl. Quaternary carbon cannot be removed as contain no a-H The more substituents placed on the nitrogen the slower it proceeds (steric hindrance) The larger the substituents are the slower it proceeds (e.g. methyl vs. ethyl). In general, small alkyl groups like Me, Et and i–Pro are rapidly removed; branching on these substituents slows it down even more Imipramine N-Dealkylation

Alicyclic Amines Often Generate Lactams

3oAmine drugs Tamoxifen Lidocaine Disopyramide Diphenhydramine Chlorpromazine Benzphetamine Brompheniramine Alicyclic Amine drugs Meperidine Morphine Dextromethorphan

Metabolism of Tamoxifen

2o & 1o Amines Generally, dealkylation of secondary amines occurs before deamination. The rate of deamination is easily influenced by steric factors both on the a-C and on the N; so it is easier to deaminate a primary amine but much harder for a tertiary amine.

Exceptions: Some 2o and 3o amines can undergo deamination directly without dealkylation.

N-Oxidation Aromatic amines 1° amines 2° amines 3° amines

The attack is on the unbonded electrons so 3o amines can be oxidized
Generally, only occurs if nothing else can happen, so it is a rare reaction Performed by both amine oxidases and hepatic MFO’s Good examples would include amines attached to quaternary carbons since they cannot be deaminated Chlorphentermine N-Hydroxylation Hydroxylamine Nitroso Nitro Phentermine Amantadine

Amides

B. Oxidation involving C-O System (O-Dealkylation)
Converts an ether to an alcohol plus a ketone or aldehyde Steric hindrance discussion similar to N-dealkylation Trimethoprim O-Dealkylation

Codeine Phenacetin Indomethacin Metoprolol Prazosin

Oxidation involving C-S System
S-Dealkylation Desulfuration S-Oxidation Steric hindrance discussion similar to N-dealkylation

Oxidative Dehalogenation
Requires two halogens on carbon With three there is no hydrogen available to replace With one, the reaction generally won’t proceed The intermediate acyl halide is very reactive

Hepatic Microsomal Flavin Containing Monooxygenases (MFMO or FMO)
Oxidize S and N functional groups Mechanism is different but end products are similar to those produced by S and N oxidation by CYP450 FMO’s do not work on primary amines FMO’s will not oxidize substrates with more than a single charge FMO’s will not oxidize polyvalent substrates Cimetidine MFMO S-Oxidation

Non-Microsomal Oxidation Reactions
Monoamine oxidase (outer membrane of mitochondria, flavin containing enzyme ) Dehydrogenases (cytoplasm) Purine oxidation (Xanthene oxidase) Monoamine oxidase Two MAOs have been identified: MAO–A and MAO–B. Equal amounts are found in the liver, but the brain contains primarily MAO–B; MAO–A is found in the adrenergic nerve endings MAO–A shows preference for serotonin, catecholamines, and other monoamines with phenolic aromatic rings and MAO–B prefers non–phenolic amines Metabolizes 1° and 2° amines; N must be attached to α-carbon; both C & N must have at least one replaceable H atom. 2° amines are metabolized by MAO if the substituent is a methyl group b–Phenylisopropylamines such as amphetamine and ephedrine are not metabolized by MAOs but are potent inhibitors of MAOs

Alcohol dehydrogenase Aldehyde dehydrogenase
Metabolizes 1° and 2° alcohols and aldehydes containing at least one “H” attached to a-C; 1° alcohols typically go to the aldehyde then acid; 2° alcohols are converted to ketone, which cannot be further converted to the acid. The aldehyde is converted back to an alcohol by alcohol (keto) reductases (reversible), however, it goes forward as the aldehyde is converted to carboxylic acid; 3° alcohols and phenolic alcohols cannot be oxidized by this enzyme; No “H” attached to adjacent carbon Ethanol Metabolism Purine oxidation Molybdenum Containing

Reductive Reactions Bioreduction of C=O (aldehyde and keton) generates alcohol (aldehyde → 1o alcohol; ketone → 2o alcohol) Nitro and azo reductions lead to amino derivatives Reduction of N-oxides to their corresponding 3o amines and reduction of sulfoxides to sulfides are less frequent Reductive cleavage of disulfide (-S-S-) linkages and reduction of C=C are minor pathways in drug metabolism Reductive dehalogenation is a minor reaction primarily differ from oxidative dehalogenation is that the adjacent carbon does not have to have a replaceable hydrogen and generally removes one halogen from a group of two or three

Reduction of Aldehydes & Ketones
C=O moiety, esp. the ketone, is frequently encountered in drugs and additionally, ketones and aldehydes arise from deamination Ketones tend to be converted to alcohols which can then be glucuronidated. Aldehydes can also be converted to alcohols, but have the additional pathway of oxidation to carboxylic acids Reduction of ketones often leads to the creation of an asymmetric center and thus two stereoisomeric alcohols are possible Reduction of a, b –unsaturated ketones found in steroidal drugs results not only in the reduction of the ketone but also of the C=C Aldo–keto oxidoreductases carry out bioreductions of aldehydes and ketones. Alcohol dehydrogenase is a NAD+ dependent oxidoreductase that oxidizes alcohols but in the presence of NADH or NADPH, the same enzyme can reduce carbonyl compounds to alcohols.

Naloxone Daunomycin Naltrexone

Reduction of Nitro & Azo Compounds

R1 and R2 are almost always aromatic
Usually only seen when the NO2 functional group is attached directly to an aromatic ring and are rare Nitro reduction is carried out by NADPH-dependent microsomal and soluble nitroreductases (hepatic) NADPH dependent multicomponent hepatic microsomal reductase system reduces the azo Bacterial reductases in intestine can reduce both nitro and azo Dantrolene Clonazepam Sulfasalazine

Reduction of Sulfur Containing Compounds
Sulfoxide reduction (Cannot reduce a sulfone) X Sulfoxide Sulfone Disulfide reduction Sulindac

Susceptibility to Hydrolysis
Hydrolytic Reactions Hydrolyzes (adds water to) esters and amides and their isosteres; the OH from water ends up on the carboxylic acid (or its isostere) and the H in the hydroxy or amine Enzymes: Non-microsomal hydrolases; however, amide hydrolysis appears to be mediated by liver microsomal amidases, esterases, and deacylases Electrophilicity of the carbonyl carbon, Nature of the heteroatom, substituents on the carbonyl carbon, and substituents on the heteroatom influnce the rate of hydrolysis In addition, Nucleophilicity of attacking species, Electronic charge, and Nature of nucleophile and its steric factors also influence the rate of hydrolysis Table: Naming carbonyl - heteroatom groups R1 R2 Name Susceptibility to Hydrolysis C O Ester Highest S Thioester Carbonate N Amide Carbamate Ureide Lowest

The Reactions Ester hydrolysis Amide hydrolysis (slower)
Carbonate hydrolysis Carbamate hydrolysis Urea hydrolysis Hydrazide hydrolysis

Drug Examples Indomethacin Prazosin Lidocaine

Drug Examples Prazosin Lidocaine

Phase II: Drug Conjugation
Attachment of small polar endogenous molecules such as glucuronic acid, sulfate and amino acids to Phase I metabolites or parent drugs Products are more water-soluble and easily excretable Attenuate pharmacological activity and thus toxicity Trapping highly electrophilic molecules with endogenous nucleophiles such as glutathione prevent damage to important macromolecules (DNA, RNA, proteins) Regarded as true detoxifying pathway (with few exceptions) In general, appropriate transferase enzymes activate the transferring group (glucuronate, sulphate, methyl, acetyl) in a coenzyme form

Glucuronic Acid Conjugation
Glucuronidation is the most common conjugation pathway The coenzyme, UDP glucuronic acid is synthesized from the corresponding phosphate UDP-glucuronic acid contains D-glucuronic acid in the a-configuration at the anomeric center, but glucuronate conjugates are b-glycoside, meaning inversion of stereochemistry is involved in the glucuronidation Glucuronides are highly hydrophilic and water soluble UDP glucuronosyltransferase is closely associated with Cyp450 so that Phase I products of drugs are efficiently conjugated Four general classes of glucuronides: O-, N-, S-, and C- Neonates have undeveloped liver UDP-glucuronosyltransferase activity, and may exhibit metabolic problem. For example, chloramphenicol (Chloroptic) leads neonates to “gray baby syndrome”

Formation of Glucuronide Conjugate

Types of Compounds Forming Glucuronides
EXAMPLES O-Glucuronide Phenols Alcohols Enols N-hydroxyamines/amides Acetaminophen morphine Chloramphenicol Propranolol Hydroxycoumarine N-hydroxydapsone N-Hydroxy-2-acetylaminoflourene

Aryl acids Salicylic acid Fenoprofen Arylalkyl acids N-Glucuronides 7-Amino-5-nitroindazole Sulfonamides Arylamines Sulfisoxazole Alkylamines 3o Amines Desipramine Cyproheptadine Meprobamate Amides

S-Glucuronides Methimazole Sulfhydryl Carbodithioic acid Disulfirum (reduced form) C-Glucuronides Phenylbutazone

Sulfate Conjugation Occurs less frequently than does glucuronidation presumably due to fewer number of inorganic sulfates in mammals and fewer number of functional groups (phenols, alcohols, arylamines and N-hydroxy compounds) Three enzyme-catalyzed reactions are involved in sulfate conjugation

Sulfation of Drugs Phenolic sulfation predominates
Phenolic O-glucuonidation competes favorably with sulfation due to limited sulfate availability Sulfate conjugates can be hydrolyzed back to the parent compound by various sulfatases Sulfoconjugation plays an important role in the hepatotoxicity and carcinogenecity of N-hydroxyarylamides In infants and young children where glucuronyltransferase activity is not well developed, have predominating O-sulfate conjugation Examples include: a-methyldopa, albuterol, terbutaline, acetaminophen, phenacetin a-Methyldopa Albuterol Terbutaline

Amino Acid Conjugation
The first mammalian drug metabolite isolated, hippuric acid, was the product of glycine conjugation of benzoic acid Amino acid conjugation of a variety of caroxylic acids, such as aromatic, arylacetic, and heterocyclic carboxylic acids leads to amide bond formation Glycine conjugates are the most common Taurine, arginine, asparagine, histidine, lysine, glutamate, aspartate, alanine, and serine conjugates have also been found

Mechanism of Amino Acid conjugation
An Acyl-CoA Intermediate Glycine Conjugate R = H Glutamine Conjugate R = CH2CH2CONH2 Drug-COOH

Brompheniramine Metabolism

Glutathione Conjugation
Glutathione is a tripeptide (Glu-Cys-Gly) – found virtually in all mammalian tissues Its thiol functions as scavenger of harmful electrophilic parent drugs or their metabolites Examples include SN2 reaction, SNAr reaction, and Michael addition

SN2 Examples

SNAr Examples

Michael Addition

Mercapturic Acid Conjugates

Acetyl Conjugation Metabolism for drugs containing a primary amino group, (aliphatic and aromatic amines), amino acids, sulfonamides, hydrazines, and hydrazides The function of acetylation is to deactivate the drug, although N-acetylprocainamide is as potent as the parent antiarrhythmic drug procainamide (Procanbid) or more toxic than the parent drug, e.g., N-acetylisoniazid Acetylation is two-step, covalent catalytic process involving N-acetyl transferase

Example of Acetylated Drugs

Methyl Conjugation Minor conjugation pathway, important in biosynthesis of epinephrine and melatonin; in the catabolism of norepinephrine, dopamine, serotonin, and histamine; and in modulating the activities of macromolecules (proteins and nucleic acids) Except for the formation of quarternary ammonium salts, methylation of an amine reduces the polarity and hydrophilicity of the substrates A variety of methyl transferase, such as COMT (catechol O-methyl transferase), phenol-O-methyltransferase, N-methyl transferase, S-methyltransferase etc are responsible for catalyzing the transfer of methyl group from SAM to RXH

Factors influencing Drug Metabolism

1-Chemical Structure : The chemical structure (the absence or presence of certain functional groups) of the drug determines its metabolic pathways. 2-Species differences (Qualitative & Quantitative): Qualitative differences may result from a genetic deficiency of a certain enzyme while quantitative difference may result from a difference in the enzyme level. 3-Physiological or disease state: 1-For example, in congestive heart failure, there is decreased hepatic blood flow due to reduced cardiac output and thus alters the extent of drug metabolism. 2-An alteration in albumin production can alter the fraction of bound to unbound drug, i.e., a decrease in plasma albumin can increase he fraction of unbound free drug and vice versa. 3-pathological factors altering liver function can affect hepatic clearance of the drug.

4-Genetic variations: 5-Drug dosing:
Factors influencing Drug Metabolism 4-Genetic variations: Isoniazid is known to be acetylated by N-acetyltransferase into inactive metabolite. The rate of acetylation in asian people is higher or faster than that in eurpoean or north american people. Fast acetylators are more prone to hepatoxicity than slow acetylator. 5-Drug dosing: 1- An increase in drug dosage would increase drug concentration and may saturate certain metabolic enzymes. 2- when metabolic pathway becomes saturated, an alternative pathway may be pursued.

6-Nutritional status: Factors influencing Drug Metabolism
1-Low protein diet decreases oxidative reactions or conjugation reactions due to deficiency of certain amino acids such as glycine. 2-Vitamin deficiency of A,C,E, and B can result in a decrease of oxidative pathway in case of vitamin C deficiency , while vitamin E deficiency decreases dealkylation and hydroxylation. 3-Ca, Mg, Zn deficiencies decreases drug metabolism capacity whereas Fe deficiency increases it. 4-Essential fatty acid (esp. Linoleic acid) deficiency reduce the metabolism of ethyl morphine and hexobarbital by decreasing certain drug-metabolizing enzymes.

7-Age: 1- Metabolizing enzymes (sp.glucuronide conjugation)are not fully developed at birth, so infants and young children need to take smaller dosesthan adults to avoid toxic effects. 2-In elderly, metabolizing enzyme systems decline. 8-Gender (sex): Metabolic differences between females and males have been observed for certain compounds Metabolism of Diazepam, caffiene, and paracetamol is faster in females than in males while oxidative metabolism of lidocaine, chordiazepoxide are faster in men than in females

9-Drug administration route: 1-Orally administered drugs are absorbed from the GIT and transported to the liver before entering the systemic circulation. Thus the drug is subjected to hepatic metabolism (first pass effect) before reaching the site of action. 2-Sublingually and rectally administered drugs take longer time to be metabolized than orally taken drugs.Nitroglycerine is ineffective when taken orally due to hepatic metabolism. 3-IVadministration avoid first pass effect because the drug is delivered directly to the blood stream.

10-Enzyme induction or inhibition Several antibiotics are known to inhibit the activity of cytochrome P450. Phenobarbitone is known to be cytochrome P450 enzyme inducer while cimetidine is cyt. P450 inhibitor. If warfarin is taken with phenobarbitone, it will be less effective. While if it is taken with cimetidine, it will be less metabolized and thus serious side effects may appear.

Study Guide What Roles are Played by Drug Metabolism? Know with structural examples Role of stereochemistry in metabolism of drugs with example of warfarin, ibuprofen and itomidate What is first pass effect; enterohepatic circulation? Why and how they occur? Drug examples Metabolisms in the intestinal mucosa CYP450, Hepatic microsomal flavin containing monooxygenases (MFMO or FMO) Monoamine Oxidase (MAO) and Hydrolases. Drugs metabolised by these enzymes and the active sites of these enzymes. Types of metabolic reaction catalyzed by these enzymes Specific CYP enzymes with the number of drugs they metabolize Few CYP family with their main functions Drug interaction basics related to metabolic enzymes

Study Guide Cont. Mechanism and routes of aromatic hydroxylation. The effects of electron donating and withdrawing groups in aromatic hydroxylation. Drug examples. What is NIH shift? Oxidation of olefins. Role of epoxide hydrolase. Can olefenic epoxide be converted to alcohol as in aromatic epoxide by NIH shift? What type of C in a drug molecule can not be hydroxylated? What is allylic and benzylic hydroxylation? Show drug examples. Show the drug examples where hydroxylation occur on Cα to C=O and C=N bonds Show the drug examples where hydroxylation occur at aliphatic and alicyclic carbon atoms. Which carbons are more easily hydroxylated? What is N-oxidatin and N-dealkylation. What enzymes are involved? How do you differentiate between N-dealkylation and deamination. Drug examples. What types of drugs generates lactams instead of causing dealkylation? What is the difference between mixed function oxidases and amine oxidases?

Study Guide Cont. What is the difference between ethanol oxidation and O-dealkylation? What is S-dealkylation, desulfuration and S-oxidation? Drug examples. How does steric factors influence S- O- and N-dealkylations? Oxidative dehalogenation with special example of chloramphenicol. Why chloramphenicol cause toxicity to the babies? What is MFMO and its active site? What types of functional groups are metabolized by this enzyme? Drug examples. MAO, dehydrogenases, xanthene oxidases and their functions with drug examples. Difference between MAO-A and MAO-B. Alcohol and aldehyde dehydrogenases, the coenzymes and the types of drugs they work on. Azo and nitro reductases, their coenzymes and the drugs they act on.

Study Guide Cont. Different types of hydrolytic enzymes. Compare rate of hydrolysis of esters, amides, carbonates and carbamates. What are different types of conjugation reactions? The enzymes and substrates involved in glucuronidation, and sulfate conjugation. Why acetaminophen is toxic to neonates? Mechanism of phenacetin and acetaminophen toxicity. What types of drugs or metabolites may form glycin conjugates? What are different mechanisms involved in glutathione conjugation? What is mercapturic acid conjugate? Mercapturic acid conjugate of acetaminophen is a sign of its toxicity – why? Mechanism of acetylation. What is slow and fast acetylator? What is COMT? What coenzymes is involved in its action? What types of drugs and/or neurotransmitters are metabolized by COMT?

THANK YOU -PHARMA STREET

DRUG METABOLISM.

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