Bio Transformation Presentation

Drug metabolism and excretion ARLENE M. DIAZ M.D, F.P.S.C.E.P PHARMACOLOGY DEPT. S.W.U- MHAM

Biotransformation

is a process wherein a drug undergoes a chemical change due to its interaction with an endogenous enzyme system (due to a nonenzymatic reactions) resulting in an increase of polarity of the drug.

Why should a drug undergoes Biotransformation?

1. to convert a drug to a more excretable metabolite

2. to convert a pharmacologically active drugto inactive metabolite 3. to convert an active drug to an active metabolite 4. to convert an inactive drug to an active metabolite 5. to convert a drug into a more toxic metabolite

Organs responsible for Biotransformation

A. Liver –Major – DMMS

B. Kidney

Organs responsible for Biotransformation

C. Lung

D. GIT (intestines)

Classification of the Chemical reactions of enzymatic biotransformation Phase I Reaction – convert the parent drug to a more polar drug metabolite by: Oxidation Reduction Hydrolysis

Oxidation-is the addition of oxygen or the removal of hyrogen from the original compound

-Is

carried out by a group of monooxygenases (oxidative enzymes found in the hepatic endoplasmic reticulum). This monooxygeneses are usually a large family of isozymes called cytochrome P450 which activates molecular oxygen using reducing equivalents such as Nicotinamide adenine dinucleotide phospate (NADPH).

Oxidation NADP+

Reduced FLA-PRO

Oxidized Drug (ROH+)

+

Drug (RH) DrugFe3+

Fe3 Step 1

Cytochrome PStep 2 450

H2O

Step 4 e-

NADP

FLA-PRO

Oxidize d

Step 3

DrugFe2+

drug Fe2+ -O2

O2

2H+

5

Reduction- the removal of oxygen or the adding of hydrogen to the original compound. Enzymes responsible, are usually 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 unstable semiquinone which undergoes autooxidation or molecular oxygen, forming free radicals (superoxide which are toxic)

Redox recycling:

Quinone

O

O2

NADPH

FLAPRO NADP+

ō

1

O O

O

SemiQuinone

superoxide

2

O2 — Molecular oxygen

Phase I - Microsomal (enzymatic) Drug Biotransformation Reaction

A. Oxidation Reaction • Aliphatic hydroxylation -Pentobarbital; Phenylbutazone • Aromatic hydroxylation – Phenytoin • Epoxidation – Benzo(a) pyrene; aflatoxin • N-Dealkylation–Diazepam,Prazepam, Methadone • O – Dealkylation – Codeine • N – Hydroxylation – 2 Acetylaminofluorene

•

Sulfoxidation -chlorpromazine

• Desulfuration – Parathion • Dehalogenation – Halothane

B. Reduction Reactions • Nitro reduction – Chloramphenicol Clonazepam • Azo reduction – Prontosil • Reductive dehalogenation – Carbon tetrachloride, DDT • Redox recycling –Doxorubicin, Mitomycin,Bleomycin

C. Hydrolysis-

the original compound is broken into smaller parts. The enzyme resposible are located in the cytoplasm, the endoplasmic reticulum and circulating in the plasma

• Ester Hydrolysis - Acetycholine, Succinylcholine, Aspirin, Procaine

• Amide - Procainamide, Lidocaine, Indomethacin • Peptide - Pro-insulin

Phase II - Conjugation RXNS RXN Type a.Glucuronidation

Enzyme UDP-glucuronyl transferases

b. Sulfation

Sulfotransferases

c. Acetylation d. Methylation e. Glutathione

Example Bilirubin, Diazepam Chloramphenicol

Esterone, Andosterone Acetaminophen Acyl COA transferases Isoniazide Sulfonamide Mythyl transferases Norepinephrine Thiouracil GSH transferases Bromobenzene Enthacrynic acid

Induction of the Drug Metabolizing Microsomal System

How Does It Occur? • Induction of the Drug Metabolizing Microsomal System • The inducer binds to the specific- receptor molecule in the cytoplasm of the hepatocyte forming an inducer-receptor complex. • The receptor-inducer complex is the translocated into the nucleous and interact with DNA resulting to transcription of specific genes. • The MRNA transcribed from DNA Subsequently translated leading to synthesis and incorporation of new cytochrome P450 into the membrane of the endoplasmic reticulum.

Significance of DMMS Induction • Inactivation or diminishing effect of

the drug(development of tolerance)

• There is an increase metabolism

of other drugs taken simultaneously by the inducer.

• There is an increase metabolism of

drugs having the same biotransformation pathway of the inducer.

Example of Drugs that Enhance drug Metabolism in humans Inducer •Chlorcyclizine

Drug whose metabolism is enhanced

•Ethychlorvynol •Glutethimide •Griseofulvin

•Steroid hormones •Warfarin Antipyrine, glutethimide, warfarin •Warfarin

Example of Drugs that Enhance drug Metabolism in humans

• Inducer Phenobarbital and other barbiturates

Drug whose metabolism is enhanced Barbiturates Chloramphenicol Chlorpromazine Anticoagulants, Cortisol, coumarin Digitoxin, Desmethylimipramine

Example of Drugs that Enhance drug Metabolism in humans • Inducer

phenobarbital BARBITURATES

Drug whose metabolism is enhanced

Doxorubicin, estradiol Phenylbutazone Phenytoin theophylline Quinine Testosterone

Example of Drugs that Enhance drug Metabolism in humans

• Inducer

Phenybutazone Phenytoin Rifampicin

Drug whose metabolism is enhanced

Aminopyrine, cortisol, digitoxin cortisol, dexamethasone,digitoxin, theophylline

Coumarin, digitoxin, methadone, Oral contraceptives, prednisone,

propranolol, Quinidine

glucocorticoids, metoprolol

Drugs that inhibit metabolism of other drugs in human Inhibitor Allopurinol, Chloramphanicol, Isoniazid

Cimetidine Dicumarol Disulfiram

Drugs whose metabolism is inhibited Antipyrine, dicumarol probenecid, tolbutamide, Chlordiazepoxide, diazepam, warfarin Phenytoin Antipyrine, ethanol, phenytoin warfarin

Drugs that inhibit metabolism of other drugs in human Inhibitor Ketoconazole Phenylbutazone

Drugs whose metabolism is inhibited Cyclosporine,astemizole, terfenadine Phenytoin, tolbutamide

Erythromycin Grapefruit juice ETHANOL CHLORDIAZEPOXIDE

Amiodarone,digoxin, antipsychotics,theophylline

terfenadine, calcium blockers DIAZEPAM,

Drugs Exertion Drugs

Absorption Distribution

Excretion Kidney Main Organ Minor Routes of Excretion GIT – Biliary/Fecal Mamary – Milk Excretion Lungs Salivary - Saliva Sweat Glands Lacrimal - Tears Hair/ Nails/ Skin

Metabolism Biotransformation Liver –Main Organ Kidney GIT Lungs

3 Major Processes Involved in the Renal Handling of Drugs 1.Glomerular Filtration of a drug at the glomerulus depends on the molecular size of the drugs

2.Tubular Reabsorption

usually occurs in the proximal tabules and generally involves organic acids such as: Penicillin, aspirin and diuretics

3.Tubular Secretion occurs in Proximal and Distal part of the nephron

Factors That Will Promote Tubular Reabsorption Ionization Ph Of Drugs Lipid Solubility

• Half Life (t1/2) is the time it takes for

the plasma cone or the amount of drugs in the body to be reduced by 50%. • Volume of distribution – relates the

amount of drugs in the body to the concentration of drug in the blood or plasma

• Clearance – measure of the body’s

ability to eliminate a drug

• Half Life of a drug is inversely related

to its clearance and directly proportional to its volume of distribution

Clinical situations resulting in increased drug half life • Diminished renal plasma flow, for ex: in

cardiogenic shock, heart failure or hemorrhage • With addition of a second drug w/c displaces

the first drug from albumin, hence, increases the volume of distribution of the drug

• With decrease excretion – renal diseases • With decrease metabolism, for Ex. –

When another drug inhibits its biotransformation

Effect of urine Ph on renal clearance for drugs that undergo tubular reabsorption

Bases Cleared rapidly by making urine more acidic Amphetamine Chloroquine Levorphanol Imipramine

Acids

cleared rapidly by making urine alkaline Acetazolamide Nitrofurantoin Phenobarbital Probenecid

Mecamylamine

Salicylates

Quinine

Sulfathiazole