bio transformation presentation

8/14/2019 Bio Transformation Presentation

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Drug metabolism andDrug metabolism andexcretionexcretion

ARLENE M. DIAZ M.D, F.P.S.C.E.PARLENE M. DIAZ M.D, F.P.S.C.E.PPHARMACOLOGY DEPT.PHARMACOLOGY DEPT.

S.W.U- MHAMS.W.U- MHAM


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BiotransformationBiotransformationis a process wherein a drug undergoes ais a process wherein a drug undergoes achemical change due to its interaction with anchemical change due to its interaction with anendogenous enzyme system (due to a nonenzymaticendogenous enzyme system (due to a nonenzymaticreactions) resulting in an increase of polarity of thereactions) resulting in an increase of polarity of thedrug.drug.


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Why should a drug undergoesWhy should a drug undergoesBiotransformation?Biotransformation?

1. to convert a drug to a more excretable metabolite1. to convert a drug to a more excretable metabolite

3. to convert an active drug to an active

metabolite

5. to convert a drug into a more toxic

metabolite

2. to convert a pharmacologically activedrugto inactive metabolite

4. to convert an inactive drug to an activemetabolite


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Organs responsible for BiotransformationOrgans responsible for Biotransformation

A.A. Liver Major DMMSLiver Major DMMS

B. Kidney


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Organs responsible for BiotransformatioOrgans responsible for Biotransformatio

C. Lung

D. GIT

(intestines)


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Classification of the ChemicalClassification of the Chemicalreactions of enzymaticreactions of enzymatic

biotransformationbiotransformation

Phase I ReactionPhase I Reaction convert the parent drug to a convert the parent drug to amore polar drug metabolite by:more polar drug metabolite by:

Oxidation

Hydrolysis

Reduction


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Oxidation-is the addition of oxygen orthe removal of hyrogen from the original

compound

-Is carried out by a group ofmonooxygenases (oxidative enzymes foundin the hepatic endoplasmic reticulum). Thismonooxygeneses are usually a large family

of isozymes called cytochrome P450 whichactivates molecular oxygen using reducingequivalents such as Nicotinamide adeninedinucleotide phospate (NADPH).


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Oxidation

H2O

OxidizedDrug (ROH+)

Drug (RH)

Oxidized

Cytochrome P-450

O2

+

e-

Step 1

Step 3

FLA-PRO

FLA-PRO

NADP+

NADP

Drug-Fe3+

Drug-Fe2+

Step 2

drug Fe2+-O2

2H+

Reduced

Fe3

Step 4

5


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Reduction- the removal of oxygen orthe adding of hydrogen to the original

compound. Enzymes responsible, areusually located in the cell cytoplasm.

Redox Recycling is a kind of reduction

for Quinone containing drugs wherein this

quinone containing drug is reduced by a single

electron and is converted to an unstablesemiquinone which undergoes autooxidation

or molecular oxygen, forming free

radicals (superoxide which are toxic)


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Redoxrecycling:

O2

O2

O

O

O

O

NADPH

FLA-PRO

NADP+

superoxide

Molecularoxygen

1 2

Quinone

Semi-Quinone


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Phase I - Microsomal (enzymatic)

Drug Biotransformation Reaction

Aliphatic hydroxylation -Pentobarbital;

Phenylbutazone

N Hydroxylation 2 Acetylaminofluorene

Sulfoxidation -chlorpromazine

Epoxidation Benzo(a) pyrene; aflatoxin

O Dealkylation Codeine

Aromatic hydroxylation Phenytoin

N-DealkylationDiazepam,Prazepam, Methadone

Desulfuration Parathion

Dehalogenation Halothane

A. Oxidation Reaction


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B. Reduction Reactions

Nitro reduction Chloramphenicol

Clonazepam

Azo reduction Prontosil

Reductive dehalogenation

Carbon tetrachloride, DDT

Redox recycling Doxorubicin,

Mitomycin,Bleomycin


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C. Hydrolysis- the original compound is broken

into smaller parts. The enzyme resposible arelocated in the cytoplasm, the endoplasmic reticulumand circulating in the plasma

Amide - Procainamide,

Lidocaine, Indomethacin

Ester Hydrolysis - Acetycholine,Succinylcholine, Aspirin, Procaine

Peptide - Pro-insulin


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Phase II - Conjugation RXNS

RXN Type

a.Glucuronidation

b. Sulfation

c. Acetylation

d. Methylation

e. Glutathione

Enzyme

UDP-glucuronyl

transferases

Sulfotransferases

Acyl COA transferases

Mythyl transferases

GSH transferases

Example

Bilirubin, Diazepam

Chloramphenicol

Esterone, Andosterone

Acetaminophen

Isoniazide

Sulfonamide

Norepinephrine

Thiouracil

BromobenzeneEnthacrynic acid


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Induction of the Drug Metabolizing Microsomal System

How Does It Occur?

Induction of the Drug MetabolizingMicrosomal System

The inducer binds to the specific- receptor

molecule in the cytoplasm of the hepatocyteforming an inducer-receptor complex.

The receptor-inducer complex is the translocatedinto the nucleous and interact with DNA resultingto transcription of specific genes.

The MRNA transcribed from DNASubsequently translated leading to synthesisand incorporation of new cytochrome P450 intothe membrane of the endoplasmic reticulum.


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Significance of DMMS Induction

Inactivation or diminishing effect ofthe drug(development of tolerance)

There is an increase metabolismof other drugs takensimultaneously by the inducer.

There is an increase metabolism ofdrugs having the samebiotransformation pathway of the

inducer.

E l f D th t


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Example of Drugs thatEnhance drug Metabolism in

humansInducer Drug whose metabolism is

enhanced

Chlorcyclizine

Ethychlorvynol

Glutethimide

Griseofulvin

Steroid hormones

Warfarin

Antipyrine,glutethimide, warfarin

Warfarin


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Example of Drugs that Enhance drugMetabolism in humans

Phenobarbital

and otherbarbiturates

Barbiturates

ChloramphenicolChlorpromazine

Cortisol, coumarin

Anticoagulants,

Desmethylimipramine

Digitoxin,

Inducer Drug whose metabolism isenhanced


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Doxorubicin, estradiol

Phenylbutazone

Phenytoin

theophylline

Quinine

Testosterone

Example of Drugs that Enhancedrug Metabolism in humans

Inducer

phenobarbital

BARBITURATES

Drug whose metabolism isenhanced

E l f D th t


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cortisol, dexamethasone,digitoxin,

theophylline

Example of Drugs thatEnhance drug Metabolism in

humansDrug whose metabolism isenhanced

Inducer

Phenybutazone

Phenytoin

Rifampicin

Aminopyrine, cortisol, digitoxin

Coumarin, digitoxin, methadone,

glucocorticoids, metoprolol

Oral contraceptives, prednisone,

propranolol, Quinidine


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Drugs that inhibit metabolismof other drugs in human

Inhibitor Drugs whosemetabolism is inhibited

Allopurinol,

Chloramphanicol,Isoniazid

Antipyrine, dicumarol

probenecid, tolbutamide,

CimetidineChlordiazepoxide, diazepam,

warfarin

Dicumarol Phenytoin

Disulfiram Antipyrine, ethanol,

phenytoin warfarin


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Drugs that inhibit metabolism ofother drugs in human

Inhibitor Drugs whose metabolismis inhibited

Ketoconazole Cyclosporine,astemizole,terfenadinePhenylbutazone Phenytoin, tolbutamide

Erythromycin Amiodarone,digoxin,

antipsychotics,theophylline

Grapefruit juice terfenadine, calcium blockerETHANOL DIAZEPAM,

CHLORDIAZEPOXIDE


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Drugs ExertionDrugs

Distribution

Absorption

Metabolism

Biotransformation

Liver MainOrgan

Kidney

Lungs

GIT

Excretion

Kidney Main Organ

Minor Routes of Excretion

GIT Biliary/Fecal

Mamary Milk ExcretionLungs

Salivary - Saliva

Sweat Glands

Lacrimal - Tears

Hair/ Nails/ Skin


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3 Major Processes Involved in theRenal Handling of Drugs

1.Glomerular Filtration

3.Tubular Secretion

2.Tubular Reabsorption

of a drug at the glomerulus depends on themolecular size of the drugs

usually occurs in the proximal tabules andgenerally involves organic acids such as:

Penicillin, aspirin and diuretics

occurs in Proximal and Distal part of the

nephron


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Factors That Will Promote

Tubular Reabsorption

Ionization

Ph OfDrugs

Lipid Solubility


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Half Life (t1/2) is the time it takes forthe plasma cone or the amount of drugs in

the body to be reduced by 50%. Volume of distribution relates theamount of drugs in the body to theconcentration of drug in the blood or

plasma Clearance measure of the bodys

ability to eliminate a drug

Half Life of a drug is inversely relatedto its clearance and directly proportional

to its volume of distribution


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Clinical situations resulting in

increased drug half life

Diminished renal plasma flow, for ex: incardiogenic shock, heart failure or hemorrhage

With decrease excretion renal diseases

With addition of a second drug w/c displacesthe first drug from albumin, hence, increases

the volume of distribution of the drug

With decrease metabolism, for Ex. When another drug inhibits its

biotransformation


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Effect of urine Ph on renal clearance for

drugs that undergo tubular reabsorption

Cleared rapidly by makingurine more acidic

Amphetamine

Chloroquine

Levorphanol

Imipramine

Mecamylamine

Bases

Quinine

cleared rapidly bymaking urine alkaline

Acetazolamide

Nitrofurantoin

Phenobarbital

Probenecid

Salicylates

Acids

Sulfathiazole

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