PhaseI Drug Metabolism Pharmaceutical Medicinal ChemistryI Dr Bilal

Phase-I Drug Metabolism Pharmaceutical Medicinal Chemistry-I Dr. Bilal Al-Jaidi Assistant Professor in Medicinal Chemistry and Drug Design Faculty of Pharmacy, Philadelphia University-Jordan Email: bjaidi@philadelphia. edu. jo

Learning Outcomes • At the end of this lesson, students will be able to: – Define what Drug Metabolism mean. – Demonstrate the different routes of Phase-I metabolism in body. – Explain the effect of Drug Metabolism on drug ‘s duration of action and activity. – Classify mechanism of drug metabolism-Phase-I. – Outline the role of drug metabolism in drug toxicity and carcinogenicity.

Drug metabolism �Refers to enzyme-mediated biotransformations (detoxication) that alter the pharmacological activity of both endogenous and exogenous compounds.

Drug metabolism • Drugs undergo a variety of chemical changes in the animal organism by enzymes of the liver, intestine, kidney, lung, plasma and other tissues. • Many enzymes take place in such biotransformations; oxidase, hydrolase, lipase, synthetase, dehydrogenase, …etc

Blood CNS Muscles Heart

Metabolism may result in: – Pharmacologically inactive drug (detoxification). – Pharmacologically active drug (bioactivation…prodrug approach). – Change the pharmacological activity (toxic effect).

The importance of studying drug metabolism: – Understanding the pharmacological and toxicological activity of drugs. – The importance of shortening the drug’s duration of action. – The complications of drug-drug interactions mainly depends on the induction or inhibition of metabolic enzymes

Drug metabolism • Can be divided into two distinct categories: – Phase-I: Reactions which introduce or unmask hydrophilic groups in the drug structure (functionalisations). – Phase-II: Reactions which conjugate the drug or its phase-I metabolite with a hydrophilic, endogenous species (conjugation reactions).

Phase-I reactions • Aliphatic hydroxylation. • Oxidation: – Oxidative Dealkylation. – Oxidative deamination. – N and S oxidation. – Alcohol/aldehyde dehydrogenase. • Reduction. • Hydrolysis.

Phase-II metabolism • Involves the following conjugation reactions that are catalyzed by transferase enzymes: – Glucuronidation. – Sulfation. – Amino acid conjugation. – Methylation. – Acetylation.

Phase-I reactions • Two general types of enzyme systems take part in these reactions: – Microsomal Mixed Function Oxidases (MFOs) • Flavoprotein, NADPH-monooxygenase • Cytochrome P 450 – Non-cytochrome oxidizing enzymes. • Xanthine oxidase • Alcohol/aldehyde dehydrogenase

General features of Cytochrome P-450 • • • A large number of families (at least 18 in mammals) of cytochrome P-450 (abbreviated “CYP”) enzymes exists as well as many subfamilies. each member catalyzes the biotransformation of a unique group of drugs some overlap in the substrate specificities.

CYP 450 Families and subfamilies Foye's principles of medicinal chemistry

CYP Biotransformations • Chemically diverse small molecules are converted, generally to more polar compounds • Reactions include: – Aliphatic hydroxylation, aromatic hydroxylation – Dealkylation (N-, O-, S-) – N-oxidation, S-oxidation – Deamination – Dehalogenation

Oxidative Phase-I involving cytochrome P-450 enzymes: • Aliphatic hydroxylation: – Mainly occur on the ultimate (ω) or penultimate (ω-1) carbon atom in the structure. – Also it occurs at an activated carbon atom, that is next to sp , sp 2 carbons:

Oxidative Phase-I involving cytochrome P-450 enzymes: • Aromatic hydroxylation:

• Aromatic epoxidation: DNA

Oxidative Phase-I involving cytochrome P-450 enzymes: • Alkene epoxidation:

Glutathione conjugation • For electrophilic drugs and metabolites:

Detoxication by glutathione adduct formation

Glutathione conjugation • Toxicity of aromatic compounds came from the formation of arene oxide during the metabolism that will be attacked by endogenous nucleophile such as proteins, DNA or RNA.

Glutathione conjugation

• O-dealkylation:

• N-dealkylation:

N-dealkylation

Oxidative Phase-I involving cytochrome P-450 enzymes: • Oxidative deamination:

Oxidative Phase-I involving cytochrome P-450 enzymes: • N-oxidation: – Mostly for primary and secondary amines as well as aromatic amines: – This gives N-oxide that will be rapidly converted to hydroxylamines.

Hydrolytic phase-I metabolism • By non-specific esterase and amidase enzymes that present in plasma, gut, liver and kidney. • It has a beneficial role in most of prodrugs that after hydrolysis inside the body release the active form of the drug.

Ester vs. Amide bond Ester bond is relatively weaker than amide bond, it will be rapidly hydrolyzed by esterase enzyme

Nucleophilic attack of hydroxide anion on ester and amide

Example Procaine Short acting local anesthetic Procainamide Long acting antiarrhythmic T 1/2 = 40 -84 second T 1/2 = 2. 5 -4. 5 hr

Hydrolytic phase-I metabolism • Examples of prodrugs activated by hydrolytic enzymes: – Dipivefrine: is a di-tertbutylcarboxy ester of adrenaline…. More lipophilic… better penetration through the corneal membrane…. then will be hydrolyzed to give the active form (adrenaline)

Why Dipifevrine has been prepared? – Adrenaline is a polar drug…. difficult access into the ocular cavity. – Adrenaline has a generalized adrenergic effect…. Many side effects such as increase blood pressure, heart rate and bronchodilation. – Dipifevrine is more lipophilic, better penetration… localized effect.

Other phase-I metabolic enzymes • Alcohol dehydrogenase and aldehyde dehydrogenase:

Other phase-I metabolism • Heterocyclic ring oxidation: • S-dealkylation:

Other phase-I metabolism • Sulfoxidation: by flavin monooxygenase

Other phase-I metabolism • Azoreduction: Antibacterial action Anti-inflammatory action

General notes regarding phase-I metabolism • Hydrolysis normally catalyzed by carboxylesterases: – Cholinesterase…. Hydrolyzes choline-like esters (such as succinylcholine), procaine and acetylsalicylic acid. – Arylcarboxyesterase. – Liver carboxyesterase

Zwitter ionic Polar Easily excreted

General notes regarding phase-I metabolism • Esters that are sterically hindered are hydrolyzed more slowly and may be appeared unchanged in urine:

General notes regarding phase-I metabolism • Amides are more stable to hydrolysis than esters…. large fraction of amide containing drugs are normally excreted unchanged.

Procaine has a short duration of anesthesia lidocaine has a long duration of anesthesia

Nucleophilic attack of HO-

Aromatic hydroxylation • The least substituted aromatic ring will be favorably oxidized, especially at the least hindered carbon atom • The activated ring will be better oxidized (the ring bearing an electron donating group)

• The least substituted aromatic ring will be favorably oxidized, especially at the least hindered carbon atom

• The activated ring will be better oxidized (the ring bearing an electron donating group) No aromatic hydroxylation

1. 2. 3. An introduction to Medicinal Chemistry by Graham L. Patrick. 4 th edition, Oxford, 2009 Wilson and Gisvolds text book of organic medicinal and pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12 th edition, Lippincott Williams and Wilkings 2011. Foyes principle of medicinal chemistry by David H. Williams, Thomas L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7 th edition, 2013.

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