Individual Differences in Drug Biotransformation

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Questions and Answers

Which drug is co-administered with ritonavir to exploit intentional drug interactions in AIDS patients?

Lopinavir

Amprenavir

Saquinavir (correct)

Nelfinavir

What effect does grapefruit juice have on cyclosporine metabolism?

Inhibits metabolism (correct)

No effect on metabolism

Enhances metabolism

Promotes excretion

Which of the following compounds is known to inhibit CYP3A4 and the P-glycoprotein transporter?

Acetaminophen

Cimetidine (correct)

Rifampin

Amoxicillin

What is the mechanism of naringenin's action against CYP3A4?

Competition for substrate binding Signup and view all the answers

At what step does an inhibitory metabolite bind tightly to CYP3A4, preventing the metabolism of other drugs?

Step 6 or 7 Signup and view all the answers

Which of the following is NOT a compound associated with inhibiting CYP3A4?

Rifampin Signup and view all the answers

What is a possible consequence of a nonsynonymous SNP in the coding region of a drug biotransformation enzyme gene?

Change in the enzyme's affinity for the drug substrate Signup and view all the answers

How does a SNP in the promoter region of a gene primarily affect drug biotransformation?

By impacting the expression level of the enzyme Signup and view all the answers

What is the result of UGT1A1 gene deletion in Crigler-Najjar syndrome?

Severe unconjugated hyperbilirubinemia Signup and view all the answers

Which variant is commonly associated with Gilbert’s syndrome?

UGT1A1*28 Signup and view all the answers

In the context of NAT-2 polymorphism, which population has the highest incidence of slow acetylators?

Swedish people Signup and view all the answers

What effect does slow acetylation have on the treatment of tuberculosis with isoniazid?

Toxic buildup of isoniazid Signup and view all the answers

What is a common effect of genetic variability on drug biotransformation?

Inconsistencies in drug effectiveness and safety Signup and view all the answers

Which of the following statements is true regarding gene deletions in drug biotransformation?

They usually involve the deletion of one member, not the whole family Signup and view all the answers

What role does genetic make-up play in drug biotransformation?

It influences enzyme structure and drug efficacy Signup and view all the answers

Why might rapid acetylators require a dosage adjustment for certain medications?

They metabolize drugs too quickly, reducing efficacy. Signup and view all the answers

Which age group is likely to have the lowest levels of drug-metabolizing enzymes?

Newborns Signup and view all the answers

What is a significant effect of drugs like Rifampin on oral contraceptive effectiveness?

They induce metabolism of contraceptive hormones, possibly leading to unplanned pregnancies. Signup and view all the answers

How do environmental factors influence the induction of drug-metabolizing enzymes?

They can vary the extent of induction based on dose and exposure. Signup and view all the answers

What commonly observed genetic variation in drug metabolism is associated with CYP2D6?

Significant variability due to genetic polymorphisms. Signup and view all the answers

What is a possible consequence of down-regulation of drug-metabolizing enzymes by cytokines during infection?

Potential for drug toxicity due to reduced metabolism. Signup and view all the answers

Which of the following dietary components can influence drug biotransformation?

Plant-based foods containing natural product inducers. Signup and view all the answers

In pregnant individuals, which drug-metabolizing enzymes typically increase in activity?

CYP3A4 and CYP2D6 Signup and view all the answers

What is a significant effect of the presence of certain SNPs on drug metabolism?

They can affect both enzyme affinity and amount of effective enzyme. Signup and view all the answers

What can the presence of weak inducers like garlic or green tea lead to in drug metabolism?

Induction of drug-metabolizing enzymes at negligible levels. Signup and view all the answers

What is the primary mechanism by which grapefruit juice interacts with cyclosporine?

Inhibiting intestinal CYP3A4 Signup and view all the answers

Which of the following drugs functions as a mechanism-based inhibitor of CYP3A4?

Erythromycin Signup and view all the answers

Which step in the CYP450 cycle involves competition for substrate binding leading to inhibition?

Step 1 Signup and view all the answers

What is a common characteristic of drugs that possess an imidazole ring in relation to CYP3A4?

They occupy the oxygen-binding site Signup and view all the answers

Which substance is primarily responsible for inhibiting both CYP3A4 and P-glycoprotein transporter?

Flavone Signup and view all the answers

How does naringenin primarily exert its effects on CYP3A4?

Through competitive inhibition Signup and view all the answers

How can SNPs in the coding region of a gene influence drug biotransformation?

By altering the enzyme protein structure, potentially changing drug affinity. Signup and view all the answers

What is a potential outcome of a SNP located in the promoter region of a gene?

Increase in the gene's product due to heightened expression. Signup and view all the answers

What condition can result from a gene deletion in the UGT1A1 gene?

Crigler-Najjar syndrome leading to severe hyperbilirubinemia. Signup and view all the answers

What is the effect of NAT-2 polymorphism in relation to isoniazid?

It influences drug levels and can result in toxicity due to slow acetylation. Signup and view all the answers

Which population is noted for having a low incidence of slow acetylators for NAT-2?

Asian and Native Americans Signup and view all the answers

How can genetic variability affect the efficacy of treatments such as irinotecan?

By modifying the enzyme expression levels of drug-metabolizing enzymes. Signup and view all the answers

What kind of effect can a nonsynonymous SNP in an enzyme have?

Change the structure of the enzyme, impacting substrate binding. Signup and view all the answers

What might be a result of down-regulation of drug-metabolizing enzymes during an infection?

Reduced metabolism, potentially leading to drug toxicity. Signup and view all the answers

Which variant is linked to potential toxicity with irinotecan treatment?

UGT1A1*28 Signup and view all the answers

What is the implication of a person being categorized as a poor metabolizer for drugs metabolized by CYP2D6?

They are at risk for toxicity with standard doses of substrates. Signup and view all the answers

Which of the following factors can lead to an increase in drug-metabolizing enzymes during pregnancy?

Increase in CYP2D6 activity Signup and view all the answers

Which external factor is known to up-regulate CYP1A2, potentially affecting drug metabolism?

Charcoal-broiled food Signup and view all the answers

What is a consequence of cytokines down-regulating drug-metabolizing enzymes during an infection?

Inhibition of the therapeutic effects of concurrent medications Signup and view all the answers

Which genotypes are associated with varying abilities in metabolizing drugs impacted by CYP2C19?

Ultra-Rapid metabolizers (URM) have a greater risk of drug dependency. Signup and view all the answers

In which situation is it particularly important to consider drug interactions due to enzyme induction?

When using herbal supplements alongside prescribed medication Signup and view all the answers

What effect does the presence of SNPs in the coding region of drug metabolizing enzymes primarily have?

Decreased stability and activity of the enzyme Signup and view all the answers

What is the expected impact of a well-nourished patient compared to a malnourished patient on drug biotransformation?

Malnourished patients exhibit decreased enzyme activity. Signup and view all the answers

What response occurs when a drug-receptor complex binds to the promoter region of a gene?

It initiates mRNA synthesis for induced enzymes. Signup and view all the answers

Study Notes

Individual Differences Affecting Drug Biotransformation

Genetic Makeup: A significant source of variability. SNPs (single nucleotide polymorphisms) in genes coding for drug-metabolizing enzymes or transporter proteins can alter enzyme structure, stability, and expression levels. This impacts the enzyme's affinity for the drug. Gene deletions (e.g., UGT1A1) can also affect biotransformation.
UGT1A1 Polymorphism: Variations lead to different outcomes:
- Gene Deletion (Crigler-Najjar syndrome): Severe, often fatal hyperbilirubinemia.
- Reduced Expression/Activity (Gilbert's syndrome): Often asymptomatic unless challenged; UGT1A1*28 is a common variant associated with this. Potential association with irinotecan toxicity.
NAT-2 Polymorphism: Affects the efficacy of isoniazid (TB treatment). Slow acetylators (higher incidence in some populations) may experience toxicity from buildup of the drug. Dose adjustment is necessary for rapid acetylators to avoid inefficacy.
Age: Drug-metabolizing enzyme activity is lower in fetuses, infants, and older adults, impacting drug clearance. Newborns have lower UGT levels, requiring cautious use of drugs cleared by these enzymes (e.g., acetaminophen).
Gender: Gender can affect drug metabolism, although specifics are not detailed here.
Pregnancy: Short-term pregnancy can temporarily influence drug metabolism.

External Factors Affecting Drug Biotransformation

Nutritional Status: Malnutrition affects enzyme levels.
Diet: Certain foods and plant-based products contain chemicals that influence drug metabolism. Some foods induce drug-metabolizing enzymes.
Drugs: Many drugs, including herbal supplements, can induce (up-regulate) specific forms of CYP450 and other drug-metabolizing enzymes. Examples include:
- Omeprazole: Induces CYP1A2 (not its primary pathway).
- Phenobarbital: A classic example of a CYP450 inducer.
- Carbamazepine: Induces CYP2 and CYP3 enzymes.
- Isoniazid: Induces CYP2E1
- Rifampin: Induces CYP3A4 and 3A5.
- Clofibrate: Induces CYP4.
- Phenobarbital & other barbiturates: Induce UGT, GST.
- Oltipraz: Induces GST.
- St. John's Wort (Hyperforin): Induces CYP3A4.
- Ethanol: Induces CYP2E1.
- Tobacco smoke, charcoal-broiled foods: Induce CYP1A2.
- Bioflavonoids, garlic, onions, green tea, black tea, preservatives (BHA, BHT, ethoxyquin): Weak inducers of various enzymes and transporters.
Consequences of Induction: Interactions between induced enzymes and other drugs can lead to unpredictable or unsafe outcomes. (e.g., Rifampin and oral contraceptives interacting)
Disease State: Infectious diseases can suppress drug-metabolizing enzymes due to cytokines. Liver disease (like cirrhosis and NASH) lowers these enzymes.

Personalized Medicine - CYP Enzymes

CYP2D6: A crucial enzyme metabolizing many N-containing drugs. Genetic variations impacting CYP2D6 affect substrate affinity, enzyme stability, and expression. "Poor metabolizers" may require lower doses, while "extensive" or "ultra-rapid" metabolizers (higher gene copies) might need higher doses to obtain a therapeutic effect. Incidence of these subsets differs geographically.
CYP2C19: Another key enzyme with high variability (especially in Asian populations), influencing responses to drugs like mephenytoin. This enzyme is also significant in caffeine metabolism in some cases.

Suppression of Drug-Metabolizing Enzymes

Cytokines: Cytokines produced during infections can suppress drug-metabolizing enzymes.
Liver Disease: Liver diseases like cirrhosis and NASH can depress drug-metabolizing enzymes.

Physiological State

Pregnancy: CYP2D6 and CYP3A4 levels increase, while CYP1A2 levels decrease.

Variability in CYP Content

Significant variability exists across CYP enzymes, with CYP2D6 showing the largest range (with a vast variety in genetic makeup and enzyme production).

Drug-Drug Interactions, Inhibition

Competition: Competition for the same pathway.
Inhibitory metabolite binding: Long-lived inhibitory metabolites can block other drug metabolism.
Oxygen binding site occupation: Drugs can block the oxygen-binding site of the enzyme, interfering with the metabolic pathway.

Food-Drug Interactions

Grapefruit Juice: Inhibits intestinal CYP3A4 and P-gp (MDR1), increasing bioavailability of certain drugs.
Bioflavonoids: Flavone and naringenin can inhibit CYP3A4 and P-gp.

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Description

Explore how genetic factors, such as SNPs and polymorphisms, influence drug metabolism and biotransformation. Learn about specific genes, like UGT1A1 and NAT-2, and their implications for drug efficacy and safety. This quiz will help you understand the relationship between genetics and pharmacology.