Organic Medicinal Chemistry Flashcards
• The biotransformation of drugs in the body
• Important in the elimination of drugs from the body
• Converts drugs to hydrophilic, inactive and nontoxic
• Has 2 Phases: Functionalization & Conjugation
Metabolism
• Introduce a polar functional group (OH, COOH, NH2, SH) by:
- Direct introduction
- Modifying/Unmasking existing functionalities
• Produce a handle on the molecule for Phase II
• Reactions: Oxidation, Reduction, Hydrolysis
Phase 1 (Functionalization)
What are the 3 Reactions in Phase 1 Functionalization in Metabolism
- Oxidation
- Reduction
- Hydrolysis
What Reactions in Phase I stated below?
• Most common Phase 1 reaction
• Undergone by Olefins, Alcohols, Aldehydes & Aromatic moieties
Oxidation
What Reactions in Phase I stated below?
• Carbonyl compounds → Alcohol derivatives
• Nitro and Azo compounds → Amine derivatives
Reduction
What Reactions in Phase I stated below?
• Commonly undergone by lactams, esters and amides
• ex. Aspirin → Salicylic acid + Acetic acid
Hydrolysis
- Attach small, Ionizable, endogenous compounds to the functional handles
- Reactions: Glucuronidation, Sulfation, Glycine & Glutamine conjugation, Glutathione, Acetylation, Methylation
Phase II (Conjugation)
What Reactions in Phase II stated below?
Coenzyme: Uridine-5’-diphospho-α-D-glucuronic acid (UDPGA)
• Transferase enzyme (TE): Glucuronyltransferase
• Most common
• Readily available supply of D-glucuronic acid
• Not yet developed in neonates
Glucoronidation
What Reactions in Phase II stated below?
Coenzyme: 3-phosphoadenosine-5-phosphosulfate(PAPS)
• TE: Sulfotransferase
• Conjugate endogenouscompounds such as steroids, heparin, chondroitin, catecholamines,thyroxine
• In neonates, it is the major process.
Sulfation
What Reactions in Phase II stated below?
- Conjugate Carboxylic acid, particularly aromatic acids & arylalkyl acid
- Glycine – common to mammals
- Glutamine – humans & other primates
- Minor pathway
Glazine and Glutamine Conjugation
What Reactions in Phase II stated below?
The first mammalian metabolite discovered from glycine conjugation
Benzoic acid → Hippuric acid
What Reactions in Phase II stated below?
• For detoxifying chemically reactive Electrophilic compounds
Glutathione
Glutathione is composed of 3 amino acids: [CGG]
- Cysteine - (-SH) is responsible for detoxification
- Glycine
- Glutamine
What Reactions in Phase II stated below?
• For termination of activity & detoxification
• Important route of primary amino groups
• Acetyl group supplier: Acetyl-CoA
• TE: N-acetyltransferase
Acetylation
Slow acetylators (Low dose)
[EEC]
Europeans
Egyptians
Caucasians