(2) Factors affecting protein binding~Hydrolysis

1. The drug itself

2. The protein itself

3.Affinity between the drug & the protein

4.Drug Interactions

5.Physiologic Condition of the patient.

Factors Affecting Protein Binding

Placental

Blood-Brain

Special Barriers:

Placental

Most small molecular weight drugs cross the placental barrier, although fetal blood levels are usually lower than maternal

Blood-Brain

It is permeable only to lipid-soluble drugs or those of very low molecular weight

“Biotransformation”

“Inactivation”

“Detoxification”

METABOLISM aka

To terminate/alter biologic

Why is drug biotransformation necessary?

Metabolism

Make the drug more polar

Phase 1 Functionalization

Phase 2 Conjugation

2 Phases

ACTIVE DRUG

PRODRUG

Drug Biotransformation Reactions

ACTIVE DRUG

Polar Metabolite

Inactive Metabolite

Active Metabolite

Reactive Metabolite

PRODRUG

Active Metabolite

Enalaprilat

Enalapril when undergoes metabolism

Isoniazid

For tuberculosis

N-acetyl Isoniazid

Acetylated form of Isoniazid

N-acetyl Isoniazid

Isoniazid when undergoes Phase 2 Acetylation

Acetylhydrazine

Isoniazid

Major metabolite

Acetylhydrazine

Isoniazid phase 1 Hydrolysis

Hepatotoxicity

When Isoniazid undergoes again Acetylation causes

Hepatocytes

Where do drug Biotransformations occur?

MAJOR SITE:

Liver

Where do drug Biotransformations occur?

MAJOR ORGAN

Extrahepatic microsomal enzymes

Hepatic microsomal enzymes

Hepatic non-microsomal enzymes

OTHER SITES OF BIOTRANSFORMATION:

First Pass Effect

First Pass Metabolism aka

First Pass Metabolism

the phenomenon whereby drugs may be metabolized following absorption before reaching systemic circulation.

Morphine

30% bioavailable

Propanolol

26% bioavailable

Enzyme Inducers

⬆ Metabolism ⬇ Pharmacologic

Enzyme Inhibitors

⬇ Metabolism ⬆ Pharmacologic act.

Tagamet

Cimetidine BN

Naringin

Grape fruit juice secondary metabolite

Carbamazepine

Phenobarbital

Phenytoin

Rifampicin

Smoking

Chronic Alcoholism

Enzyme Inducers

Cimetidine

Ketoconazole

Chloramphenicol

Disulfiram

Grapefruit Juice

Acute Alcoholism

Enzyme Inhibitors

Phase 1 Functionalization

Makes drug more polar, adds a chemically reactive group (a handle) permitting conjugation (functionalization)

Adds an endogenous compound increasing polarity

Phase 2 Conjugation

Phase 1 Functionalization Reactions

reactions that convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as -OH, -SH, or –NH2.

Oxidation

Lost of electron

Reduction

gain electron

1A2

Substrates

Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin, tacrine, tamoxifen, theophylline, warfarin

Smoking, charcoal

Inducers

1AZ

Galangin, furafylline, fluvoxamine

Inhibitors

1AZ

2A6

Substrates

Coumarin, tobacco nitrosamines, nicotine

Rifampin, cotinine and 2’-hydroxynicotine) phenobarbital

Inducers

2A6

Tranylcypromine, methofuran, methoxsalen

Inhibitors

2A6

Hydroxylation

(Phenytoin)

N-Dealkylation

(Morphine)

O-Dealkylation

(Codeine)

N-Oxidation

(Nicotine)

S-Oxidation

(Thioridazine)

Deamination

(Amphetamine)

Xanthine oxidase

Hyopoxanthine → Xanthine

Enzyme

Uric acid

Xanthine →

Uric acid

Waste product of urine

Have tendency to form crystalls

Flavin Monooxygenase (Ziegler’s enzyme)

Addition of oxygen

Epinephrine

Amine Oxidases

Xanthine Oxidase

Flavin Monooxygenase (Ziegler’s

enzyme)

Amine Oxidases (Epinephrine)

Dehydrogenase(Ethanol)

Non CYP 450 Mediated

Ethanol

Dehydrogenase

Aldehyde

→ primary alcohol

Ketone

→ Secondary alcohol

Monoamine oxidase

Epinephrine metabolized by

Acetohexamide

Carbonyl reduction

Sulfazalazine

Azoreduction

Clonazepam

Nitroreduction