Pmcol

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Prodrug:

Back 1

substance that takes inactive
drug and makes it active.

Front 2

Drug metabolizing enzyme

Back 2

facilitates movement of drug (excretion)

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Phase I Metabolism

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Functionalism step, makes drug easier to excrete by making it more polar, thus polar for elimination in urine.
Main goal is to make drug susceptible for Phase II.

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CYP 3A4

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Most common liver enzyme in humans.

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CYP 2D6

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Metabolizes a lot, but contributes less liver metabolism than 3A4.

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Hepatic Profile

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Variety in drug response (up to 200 fold difference)

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p450

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Hemoprotein - ives cell a red color, absorbs at 450 nm.
Complexing enzyme with CO, Fe. (Redox)
Substrate is drug-ferric complex.

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p450 Reaction

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Redox reaction, add a single O from O2 via complex reaction scheme to yield drug-ferric complex.

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Inter-person variability.

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Liver p450 enzymes profiles differ between people to cause greatest variability between inter-person variability.

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genetic polymorphism

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gene exists in 2+ forms.
product enzyme has substantial deletion or minor.
Major difference: deletion
Minor difference: substitution

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Result of genetic polymorphism

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Increased/decreased/inactive activity.

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CYP 2D6 wildtype

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Extensive metabolizers.
Steeper slopes.
Bioavailability is the same.

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CYP 2D6 altered

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Poor metabolizers.
Less steep slopes.
Bioavailability is the same.

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CYP 2D6 variation

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Racial
2+ different alles

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Reducing CLINT

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Reduces Elimination

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Endogenous factor

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P450 activity foes down with age.
1/2 life/elimination and elimination is similar between ages.
Peak is higher for old people: higher bioavailabiliyu.

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Propanolol

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High extraction ratio.

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Phenacetin

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Smokers have reduced peak, bioavaivlity is reduced, drug cleared more quickly.

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CYP induction

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Environment, diet.

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CYP 1As induction

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cigarettes, charred beef (transcriptional level - more protein), cruciferous vegs.

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CYP 2Bs induction

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Pesticides, barbiturates.

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CYP 3As induction

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Many drugs, including St. john's wort. nduces its own metabolism, expresses more enzymes.

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CYP 3A4 inhibition

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Irreversible knock up by grapefruit juice.
Risk: drug not cleared at normal speed.

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Polypharmacy

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Competitive inhibition for metabolism.
1+ drugs fighting for 1 enzyme, can increase bioavailability.

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3A4 induction

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3A4 induces its own metabolism, expresses more enzymes.

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Phase II reactions

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Glucoronidation, sulfation, acetylation, glutathionylation

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glutathionylation

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Detox, deals with damaging species (cancer, cell damage)
Cross talk

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UDP Glucoronosyl transferase (UGT)

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high levels in liver smooth ER
Forms glucoronide (O-UDP) conjugate (MW> 400, excrete in bile)
Next to p450, so can quickly take its metabolites and react.

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Enterohepatic recirculation

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Generate glucorynite, pass to intestines.
Intestinal enzymes remove glucoronide, drug reabsorbed into liver, then systemic circulation.

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Bile salts

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Eliminate fat cells, reuse bile salts 20 times.

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Disulforam

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Glucoronation. Makes alcoholics sick.
Direct Phase II, get 2 products.

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Sulfanialmide

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Add glucuronide to amine, sulfonamide or both.

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UDP endogenous ligand

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Coagulates and eliminates bilirubin.

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Infant jaundice

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UDP not developed yet, can't get eliminate bilirubin.

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Morphine

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Glucoronidation on -OHs.

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Glucoronidation

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Morphine, salicyclic acid, sulfinamide, disulfiram.
UDP enzyme.

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Sulfation

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Sulfotransferase enzyme acts on Phase I metabolites.
Product is water soluble sulfate.
But, sulfate is inert, must form high energy complex large molecule too.
Sulfate + ATP -> ADP sulfate + phosphate -> PAPs.

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PAP

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Sulfate + ATP + P is reactive ligand for sulfonation reactions.

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Sulfutransferase ligands

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Binds most drugs with high affinity.
BUT when [drug] is high, glucoronidation is preferred.

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Acetylation

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Occurs in Kupffer cells of liver.
Acretyl coA req, for all N-groups ntibacterial drugs.
**Product less soluble than parent drug.
NAT-1, NAT-2.
Adding on CoASH

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Acetylation Endogenous Roles

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Biosynthesis of glucotrienes for immune reposne.

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Solubility of Acetylation CoASH conjugates

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Some have low solubility, decreased solvation results in crytsals, kidney damage.

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NAT-2

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Acetylation enzyme, genetic polymorphism.
Low peaks = slow acetylators vs High peaks = fast acetylators.

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Predict kidney damage from acetylators

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Fast acetylators more likely to get kidney damage.

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Acetylator Test

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Take drug in the morning, collect urine all day.
2 tubes, one with HCl, boil, hydrolyzing n-acetal bonds to get parent drug back.
Tube 1 is acetyl. and non.acetyl.
Tube 2 is non-acetyl. only, brightness of purple dye.
% drug excreted in acetyl.form: well above or below 70%.

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Gluthathinione Conjugation

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1' Protection mechanism against electrophilic species.
Glutathione S-transferase (GST)

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Electrophilic species

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Damage cells, ie DNA and cancer.

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Glutathione S-transferase (GST_

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Soluble enzyme in liver and kidney.
Forms electrophile and gluthathione (tri-peptide) complex.

Front 49

Glutathinione

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Glu-cys-gly. Tripeptide ligand of gluthathinione conjugations.

Front 50

Tylenol

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Liver Damage
Small bit turns to NAPQI, electrophilic toxin, causes irreversible damage.

Front 51

Tylenol Mechanism

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NAPQI is electrophlic toxin, conjugates with gluthathinone, but [gluth] is limited.
Over dosing = depleting [gluth]
Metabolites in urine:
2 peptidase enzymes cut: 1. Glu 2. Gly 3. Cys
N acetyl transferase (NAT) recognizes amine to make NAPQI-mercapturate.

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Tylenol safety mechanism

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Suicidal people - Capsule has n-acetyl Cys ot Met, can conjugate NAPQI without enzyme.

Front 53

Chirality of warfarin

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Same 1' structure, not all fits into binding pockets.

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Chirality

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Different pathways, rates and K elimination.

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Racemic Mixtures

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Must test both, can't administer 1 only because body enzymes synthesize stereoisomer.