Metabolism in lead selection Flashcards
Explain phase 1 and Phase 2 metabolism
Phase 1 metabolism is the first step in the process and involves the oxidation, reduction, or hydrolysis of the foreign substance by enzymes such as the cytochrome P450 family. This process usually produces more reactive and potentially toxic intermediates that can cause damage to the body. However, Phase 1 metabolism can also produce more polar and water-soluble metabolites that are easier to excrete from the body.
Phase 2 metabolism, on the other hand, involves the conjugation of the Phase 1 metabolites with other molecules such as glucuronic acid, sulfate, or glutathione. This step is necessary to further increase the water solubility of the metabolites and facilitate their elimination through urine or feces. Phase 2 metabolism is carried out by a variety of enzymes such as UDP-glucuronosyltransferases, sulfotransferases, and glutathione S-transferases.
Phase 1 metabolism
Oxidation: The first step in Phase 1 metabolism is the introduction of a hydroxyl group (-OH) into the foreign substance by the action of the cytochrome P450 (CYP) family of enzymes. This reaction requires oxygen and NADPH (nicotinamide adenine dinucleotide phosphate) as cofactors, and it results in the formation of a more polar and water-soluble metabolite.
Reduction: The next step in Phase 1 metabolism is reduction, in which electrons are added to the foreign substance by enzymes such as reductases. This reaction reduces the activity of the substance, making it less toxic.
Hydrolysis: Hydrolysis is a less common type of Phase 1 metabolism, in which a covalent bond in the foreign substance is cleaved by the action of enzymes such as esterases or amidases. This reaction often results in the formation of more polar and water-soluble metabolites.
Dealkylation: Dealkylation is a type of oxidation reaction in which a methyl or ethyl group is removed from the foreign substance by the action of enzymes such as CYP2D6 or CYP3A4. This reaction results in the formation of more polar and water-soluble metabolites.
Deamination: Deamination is a type of oxidation reaction in which an amino group (-NH2) is removed from the foreign substance by the action of enzymes such as CYP2D6 or CYP3A4. This reaction results in the formation of more polar and water-soluble metabolites.
Desulfuration: Desulfuration is a type of oxidation reaction in which a sulfur group is removed from the foreign substance by the action of enzymes such as CYP2D6 or CYP3A4. This reaction results in the formation of more polar and water-soluble metabolites.
Phase 2 metabolism
Glucuronidation: Glucuronidation is the most common type of Phase 2 metabolism, accounting for approximately 35% of all Phase 2 reactions. In this reaction, a glucuronic acid molecule is added to the Phase 1 metabolite by the action of UDP-glucuronosyltransferase (UGT) enzymes. This reaction results in the formation of a more polar and water-soluble metabolite that can be easily excreted in the urine or bile.
Sulfation: Sulfation is another common type of Phase 2 metabolism, accounting for approximately 30% of all Phase 2 reactions. In this reaction, a sulfate group (-SO3) is added to the Phase 1 metabolite by the action of sulfotransferase (SULT) enzymes. This reaction also results in the formation of a more polar and water-soluble metabolite that can be excreted in the urine or bile.
Methylation: Methylation is a less common type of Phase 2 metabolism, accounting for approximately 15% of all Phase 2 reactions. In this reaction, a methyl group (-CH3) is added to the Phase 1 metabolite by the action of methyltransferase enzymes. This reaction can increase the polarity and water solubility of the metabolite, making it easier to eliminate from the body.
Acetylation: Acetylation is another less common type of Phase 2 metabolism, accounting for approximately 10% of all Phase 2 reactions. In this reaction, an acetyl group (-COCH3) is added to the Phase 1 metabolite by the action of acetyltransferase enzymes. This reaction can also increase the polarity and water solubility of the metabolite, making it easier to eliminate from the body.
Amino acid conjugation: Amino acid conjugation is a rare type of Phase 2 metabolism that involves the addition of an amino acid molecule to the Phase 1 metabolite by the action of amino acid transferase enzymes. This reaction can increase the polarity and water solubility of the metabolite, making it easier to eliminate from the body.
hERG
hERG = ‘human ether-a-go-go related gene’
▪ Potassium ion channel
▪ If channel which is regulating heart beat is activated the
flow of K+ out of cell is slowed down, lengthening the time
required to repolarise the cell (QT interval, from 300 ms to
320 ms)
▪ Can lead to fatal arrhythmias
