Drug Metabolism - Phase II

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Transcript of Drug Metabolism - Phase II

Drug Metabolism

PhasePhase-II Reactions

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Phase II reactions are conjugation reactions or synthetic reactions. Phase I reactions introduce or expose a functional group to the drug molecule, i.e., either a polar functional group is placed in the molecule or polar constituent is revealed. Once the polar part is exposed then Phase II reaction may occur

Phase I DRUG

Metabolite

Phase II Metabolite Phase II

E x c r e t i o n

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Conjugating reagents are derived from biochemical compounds involved in carbohydrate, fat and protein metabolism. Phase II reaction produce water soluble compounds that can be excreted through urine or bile.

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GLUCURONIDATIONQuantitatively the most important phase II pathway for drugs and endogenous compounds (bilirubin). It is the conjugation reaction between Uridine diphosphate glucuronic acid (UDPGA) [a-glucuronide] and drugs containing OH, -COOH, -NH2 and SH. Reaction is mediated by microsomal enzyme glucuronyltransferase (b-glucuronide is formed). O-glucuronide conjugation excreted through bile to gut b-glucuronidase break the conjugate possible reabsorption of drug Entro-hepatic circulation of drug long elimination half life. Ester-glucuronide get hydrolyzed in urine or plasma to form parent drug. E.g. clofibrate

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N-glucuronidation of sulfanilamide

Occurs with amines (mainly aromatic ), amides and sulfonamides`

O-glucuronidation of Morphine

O-glucuronidation occurs by ester linkages with carboxylic acids, phenols and alcohols

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S-glucuronidationExample glucuronidation of Disulfiram

Conjugation with other sugar Conjugation with glucose, xylose, ribose and arabinose are also possible. Glucuronidation is the major sugar conjugation. Example: 2-hydroxy nicotinic acid conjugates with ribose All sugar conjugates are water soluble and excreted through urine.

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SULFATIONCommon for phenols, alcohols, amines and lesser extent to thiols. Conjugating agent (i.e., sulfate donor) is 3phosphosadenosine-5phosphosulfate (PAPS) Enzymes involved areNon-specific phenol, alcohol and arylamine transferases Specific steroid transferases

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Sulfate conjugates are water soluble and have high renal clearance.

MINOXIDIL (inactive)

MINOXIDIL N-O-SULFATE (active metabolite)

H 2N N O

N

N

H 2N

N

N

NH

2

O N HO S O NH O

Minoxidil

Minoxidil-sulfate

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Methylation Non-specific methyltransferases methylate drugs with the help of S-adenosylmethionine (SAM) to form methyl-conjugates. SAM is produced from L-methionine and ATP under the influence of enzyme L-methionine adenosyltransferase. methyl-conjugates are less polar and thus the metabolite is not easily excreted from body.

O

O

N H C HS N H S

N

N H

THIOURACIL

S-METHY-THIOURACIL

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Acetylation Common for aromatic amines and sulfonamides, requires Acetyl-CoA and enzyme N-acetyl transferases. It can take place mainly in Kupffer cells of liver. This reaction can also take place reticuloendothelial cells of spleen, lungs and gut.

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Acetylated product are less polar than parent compound. This will increase the elimination half life of the metabolite, also renal toxicity (e.g. : acetylatedsufonamide). In the case of active metabolite, this long half life is important. (procainamide Nacetylprocainamide). N-acetyltransferase exhibit genetic polymorphism.E.g. Isoniazid inactivation

CO-NH-NH2

CO-NH-NH-CO-CH3

N

N

ISONIAZID

ACETYL ISONIAZID

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AMINO ACID CONJUGATION It is a special form of acetylation. Aromatic acids are activated by combining with ATP to form CoA derivative then it undergoes the amino acid conjugation. Amino acid involved are glycine, glutamine, ornithine, arginine and taurine. Bile acids also undergo amino acid conjugation.

RCOOH + CoA-SH ATP

RCO-S-CoA

N-acyltransferase RCO-S-CoA + NH2CH2COOH Glycine(mitochondria)

RCONHCH2COOH Glycine conjugate

COOH

CO-S-CoA

+ CoA- H

B NZOIC ACIDCO-S-CoA CO-NH-CH2-COOH

+ NH2CH2COOH G CINE HIPP IC ACID

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GLUTATHIONE CONJUGATION Glutathione, glutamyl-cysteine-glycine is recognized as a protective device against toxic electrophilic compounds. It reacts non-enzymatically and enzymatically via glutathionine-S-transferase, through nucleophilic sulfhydryl group with electrophilic oxygen intermediates. Compounds conjugate with glutathione includes epoxides, haloalkanes, nitroalkanes, alkenes and aromatic halo- and nito- compounds.

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Glutathione-S-transferase are found in liver, kidney, gut and other tissues. Reaction occurs in 4 steps1. 2. 3. 4. Drug+Glutathione forms drug conjugate Removal of glutamyl by glutamyl transpeptidase Removal of glycine by peptidase N-acetylation of cysteine conjugate forms N-acetylated cysteine(mercapturic acid)

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Glutathione conjugate undergoes biliary secretion, but in gut it breaks down by C-S lyase produced by intestestinal microflora. This results SH transfer and its methylation. Methylated drug is reabsorbed and reaches liver. In liver oxidation occurs ant methylthio-derivative is excreted.Example : caffeine

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Saturation of this pathway will lead to accumulation of electrophilic intermediates. These are capable of binding with hepatic cellular macromolecules and will cause cell damage. N-acetylcysteine, which containing sulfhydral group is used as antidote for toxicity.Acetaminophen

H C C H

COOR

H C C

COOR

COOR

Glutathione

COOR

Esters f maleic acid

Glutathione conjugate

Phase I

Phase II

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FATTY ACID CONJUGATION This involved in the conjugation of stearic and palmitic acids. 11-hydroxy-D9-tetrahydrocannabinol undergoes this type conjugation.

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CONDENSATION REACTIONS These reactions are purely chemical and common among aldehydes and amines. Dopamine + 3,4-dihydroxyphenyacetaldehyde tetrahydropapaveroline (potent dopamine antagonist)

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Phase II reactions produces more polar product, which can be excreted easily. Major reactions are Glucuronide conjugation, Acetylation and Sulfation. Glucuronide conjugation may increase half-life. Products are generally more water soluble. These reactions products are ready for (renal) excretion. Phase II reactions are possible only for compounds having polar group. This is important for lipophilic drug, determines the rate of excretion.

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Reaction Glucuronidation Sulfation Methylation Acetylation Amino acid conjugation Glutathione conjugation Fatty acid conjugation Condensation

Enzyme UDPglucuronyltransferase Sulfotransferase Methytransferase Acetyltransferase

Functional group -OH, -COOH, NH2, -SH -OH, SO2NH2, NH2 -OH, -NH2 -OH, SO2NH2, NH2, -COOH -COOH Epoxides, organic halides -OH Aldehydes and amines -

Example Morphine Minoxidil Thiouracil Isoniazid Benzoic acid Maleic acid 11-hydroxy-D9tetrahydrocannabinol Dopamine

---Glutathione-Stransferase ----

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