Drug Metabolism Flashcards
In general, why is drug metabolism necessary?
Metabolism converts lipohpilic compounds to more polar, water-soluble chemicals that are more readily excreted.
List five locations where biotransformation occur?
- Liver
- Kidney
- intestinal lumen
- intestinal cells
- lung cells
Phase I modifications are important for making the molecule sufficiently polar, even though it may not be enough for excretion. Describe the mechanism of action for Phase I modifiers:
Introduces functional groups or unmasks functional groups including -OH, -NH2, -SH
What types of substrates are used in Phase II reactions that will increase the size and polarity of the molecules, allowing for excretion, and usually, inactivity.
Endogenous substances like
- glucouronic acid
- acetic acid
- sulfuric acid
- glutathione
- amino acids
- methyl group
T or F: All drugs must follow Phase I reations and then phase II reactions for complete elimination/inactivity?
False. substances may follow Phase I by Phase II, may use Phase II first, then Phase I (especially if the substance already has a functional group attached), or may use on or the other.
What is the principle metabolic organ responsible for biotransformation?
Liver
T or F: The intestine metabolizes some drugs to a greater extent than the liver?
True (via enzymes in the intestinal epithelial cells)
Phase I enzymes are mixed function oxidases (MFO) and REQUIRES a reducing agent, being NADPH. Enzymes required for Phase I reactions include:
- NADPH-cytochrome P450 reductase
- cytochrome P450
Make note of the importance of NADPH. Recall, that disease like G6PD where there is a lack of NADPH, there may be adverse effects from lack of drug metabolism due to impaired antioxidant mechanisms (i.e. may develop acute hemolytic disease)
50% of all drugs are metabolized by what group of enzymes?
CYP3A4/5
What type of reactions characterize those which occur in Phase II reactions?
Transferase reactions. GST= glutathione S-transferase UGT= UDP-glucuronosyltransferase SULT= sulfotransferase TPMT= thiopurine methyltransferase NAT = N-acetyltransferase
What are the main locations for Phase I and Phase II enzymes?
Phase I- Endoplasmic reticulum
Phase II- cytosol
T or F: endogenous substrates for conjugation reactions are primarily dietary substituents?
True
T or F: Phase I and Phase 2 enzymes may compete for the same substrate?
True
Due to the overlap of enzymes involved in drug metabolism, meaning that multiple enzymes can have affinity for the same substrate, potential for drug interactions develop.
Describe enzyme induction:
Induction: With REPEAT drug administration, some enzymes can be enhanced (increases potency= accelerates drug metabolism) or their rate of degradation is reduced.
CYP450 induction requires enhanced transcription and translation.
Due to the overlap of enzymes involved in drug metabolism, meaning that multiple enzymes can have affinity for the same substrate, potential for drug interactions develop.
Describe enzyme induction:
Induction: With REPEAT drug administration, some enzymes can be enhanced (increases potency= accelerates drug metabolism) or their rate of degradation is reduced.
CYP450 induction requires enhanced transcription and translation.
Due to the overlap of enzymes involved in drug metabolism, meaning that multiple enzymes can have affinity for the same substrate, potential for drug interactions develop.
Describe enzyme inhibition:
CYP450 induction requires enhanced transcription and translation.
Usually, if a drug inhibits CYP450, it is due to binding the heme iron of the enzyme and making it catalytically inactive.
Mutations in what three regions of the DNA will lead to changes in the DNA that may cause polymorphism and influence pharmacogenetics?
Coding region
Promoter region
Intronic region (if affecting splicing)
Regarding pharmacogenetics, variability in drug half-life (drug elimination) can be due to what?
Multiple gene products that can affect drug metabolism
pharmacogenetics factors may involve enzymes, transporters, or receptors.
T or F: Most pharmocogenetic traits are multi genetic?
True
Some pharmacogenetics traits can alter the Km and Vmax of an enzyme-substrate complex. Explain what would be the result of alteration of either:
Altered Km = Km is usually increased as the affinity for the enzyme-substrate complex is decreased.
Altered Vmax = Vmax is usually decreased, as there may be less receptors available due to protein instability
What enzyme is inhibited by grapefruit juice?
CYP3A
