Phase 1 Metabolism (Pharmaceutical Medicinal Organic Chemistry)

Metabolism or Biotransformation

Plays a central role in the elimination of drugs and other foreign compounds (xenobiotics) from the body.

Parent drug

This can be active or inactive drug.

Functionalization phase

Metabolic pathways: Phase 1 reaction also called as?

1. Oxidation

2. Reduction

3. Hydrolysis

Polar functional groups are introduced into molecule or unmasked by? (3)

To make the drug polar

Main goal of Phase 1?

1. Alcohol

2. Acid

3. Amino

4. Sulfhydryl

4 polar functional groups.

1. Hydroxylation

2. Aromatic Hydroxylation

Reaction if Alcohol group is added. (2)

1. Direct Introduction of functional group

2. Modifying or Unmasking existing functionalities

Phase 1 is achieved by? (2)

1. Aldehyde

2. Acid

Primary alcohol can be oxidized to? (2)

1. Aldehyde

2. Primary Alcohol

Acid can be reduced to? (2)

Ketone

Secondary alcohol can be oxidized to?

Secondary Alcohol

Ketone can be reduced to?

Oxidation

No Hydrogen there’s no______?

No

Can Tertiary Alcohol can be Oxidized?

No

Can Ketones can be oxidized?

Ester

Acid reacts to Alcohol form? [Esterification]

1. Acid

2. Alcohol

Ester react to Water form? (2) [Ester Hydrolysis]

Amide

Acid react with Amine form?

1. Acid

2. Amine

Amide react with Water form? (2) [Amide Hydrolysis]

Ether

Alcohol react with Alcohol form?

Microsomes

Form in vitro after cell homogenization and formation of ER.

Mixed Function Oxidase or Monooxygenase

Smooth microsomes contain a class of oxidative enzymes called?

Nicotinamide adenine dinucleotide phosphate (NADPH)

MFO or Monooxygenase require what reducing agent?

1. Flavoprotein or NADPH-cytochrome P450 reductase

2. Cytochrome P450

MFO or Monooxygenase consist of 2 enzymes what are this?

Flavoprotein

Carries electrons from NADPH to CYP450

Reactive Oxygen Species (ROS)

This is a free radicals which should be stabilized or else, this can cause cellular damage.

1. Phenyl

2. Para

3. Phenolic

The 3PS.

Arene oxide

Forms Toxic intermediate metabolite. (An epoxide, Cyclic ether and ROS)

Arenols

NIH shift leading to the formation of?

1. Spontaneous rearrangement (NIH shift)

2. Hydration (Epoxide hydrase)

3. Glutathione conjugation

3 ways to stabilize the arene oxide.

1. Flavin mononucleotide (FMN)

2. Flavin adenine dinucleotide (FAD)

One mole of Flavoprotein contains. (2)

Aromatic Hydroxylation

Major route of metabolism for many drugs containing phenyl groups.

Para position

Hydroxylation occurs at what position?

Oxirane

The metabolic oxidation of olefinic carbon double bonds leads to formation of?

Epoxide

Susceptible to enzymatic hydration by epoxide hydrase to form trans-1,2-dihydrodiols.

1. Cyclohexene oxide

2. Trichloropropene

This compound inhibit the formation of stable complex of Epoxide. (2)

Benzylic Carbon

Is the carbon next to benzene ring.

Carbinol

Addition of OH group will take place on the benzylic carbon forms?

Steric Hindrance

Occurs when bulky groups within a molecule prevent or slow down chemical reactions by physically blocking the approach of reactants to reactive sites. Crowded