Drug Metabolism LO Flashcards
Lecture 5 Svensson
Name the primary organ involved in drug metabolism
Primary organ is liver because it has a smooth endoplasmic reticulum of liver cells, high concentration of drug metabolizing enzymes, and first organ exposed to compounds absorbed in the gut. Other important organs include GI tract, lungs, kidneys, brain, and skin
Define and differentiate the two phases of drug metabolism
Phase 1: In this phase, the drug undergoes chemical changes, like adding oxygen (oxidation) or adding an -OH group (hydroxylation). These changes either create new functional groups or make existing ones more accessible, preparing the drug for the next phase. Phase 1 reactions typically are catalyzed by CYP450 monooxygenase using NADPH and oxygen.
Phase 2: Here, a polar (water-friendly) group, such as acetyl or sulfate, is attached to the drug. This (glucoride) “conjugation” makes the drug easier for the body to eliminate.
Given a specific CYP450, identify the family, subfamily individual gene, and allelic variant component.
CYP2D6*1A
CYP (superfamily) 2 (family) D (subfamily) 6 (individual gene) * 1A (allele)
Differentiate between the mechanism of reversible and irreversible CYP450 inhibition
Reversible: compete with other substrates for occupancy of active site of the same CYP enzyme similar to a receptor antagonist. the inhibitor (a substance) temporarily attaches to the CYP450 enzyme. It blocks the enzyme from working but can detach after a while, allowing the enzyme to work again. It’s like a temporary “pause button” on enzyme activity.
Irreversible: Mechanism based inhibition. The inhibitor binds permanently to the CYP450 enzyme, usually by forming a strong chemical bond. This permanently deactivates the enzyme, stopping it from working for good. It’s like a “stop button” that permanently disables the enzyme’s function. The body has to make new enzymes to restore normal activity.
Explain why an enzyme inducer may increase the metabolism of drugs metabolized by different cytochromes P450.
An enzyme inducer speeds up the body’s process of breaking down drugs. It does this by making the body produce more of certain enzymes (like the cytochrome P450 enzymes) in the liver, which are responsible for drug metabolism.
When there are more of these enzymes, drugs get processed and removed from the body faster. This doesn’t just affect one type of enzyme but can increase multiple types, so any drug broken down by these enzymes will also be cleared out more quickly.
Provided a reaction, name the phase 2 metabolic process ( i.ec sulfonation, glucuronidation)
Glucuronidation: The body attaches a glucuronic acid (a sugar-like molecule) to the drug. This makes the drug more water-soluble, so it can be easily removed in urine or bile.
Sulfation (Sulfonation): The body adds a sulfate group (a sulfur-based group) to the drug. This also makes it more water-soluble, helping with easy excretion.
Acetylation: An acetyl group (a small, carbon-based group) is added to the drug. This doesn’t increase water solubility much but can make the drug inactive and ready for elimination.
Methylation: The body adds a methyl group (a -CH₃ group) to the drug. This can change the drug’s activity or make it ready for excretion, though it doesn’t necessarily make it more water-soluble.
Glutathione Conjugation: A molecule called glutathione (GSH) attaches to the drug, especially if it’s potentially toxic. This process protects the body by neutralizing harmful parts of the drug and making it ready for excretion.
Amino Acid Conjugation: The drug combines with an amino acid (like glycine or glutamine). This makes the drug more water-soluble, helping the kidneys excrete it more easily.
Explain why genetic variation in metabolism often is not the most important factor in determining variation in drug concentration s and, ultimately, clinical response.
Genetic differences in metabolism do affect how fast or slow someone processes a drug, but they’re often not the main reason why people have different responses to the same drug. Here’s why:
Other Health Factors: Things like age, liver and kidney health, and overall wellness can have a bigger effect on drug levels than genetics.
Drug Interactions: If someone takes multiple medications, these can interact and change drug levels more than genetic differences. Some drugs can speed up or slow down the breakdown of others.
Lifestyle Choices: Diet, alcohol, and smoking can all change how the body processes drugs. For instance, alcohol can make the liver process some drugs faster or slower.
Drug Type and Dose: The form of the drug (pill, injection, etc.) and the dose matter a lot for how quickly and effectively it works, sometimes more than genetic factors.
Sensitivity to the Drug: Even if two people have the same drug level, one person might respond more strongly than the other. This depends on how sensitive their cells are to the drug, which can vary widely.
