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Questions and Answers
What is the consequence of phase 2 metabolism conjugation in the context of biliary clearance of drugs?
The conjugated drugs pool in the bile ducts and enter the GIT, where the conjugate can be cleaved off, recycling the drug back into its active form.
How does the build-up of toxic intermediate in paracetamol overdose affect the enzyme system?
The enzyme system becomes saturated, hindering the breakdown of the drug.
What is the characteristic of cytochrome P450 super family of enzymes in phase 1 drug metabolism?
They catalyse the oxidative metabolism of xenobiotics and have broad substrate specificity.
What is the outcome when a prodrug is metabolized?
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What is the consequence of few enzymes being present for many drugs?
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Where are liver drug-metabolizing enzymes usually embedded?
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What happens to a drug once it is secreted into the bile ducts?
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What is the importance of functional groups in phase 2 metabolism?
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What is the primary reason for the differing substrate specificity of cytochrome P450 enzymes?
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What is the role of NADPH–P450 reductase in the enzyme reaction of cytochrome P450?
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How do multi-allelic polymorphisms affect the activity of cytochrome P450 enzymes?
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What is the effect of smoking on the activity of cytochrome P450 enzymes?
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How do citric fruits affect the activity of cytochrome P450 enzymes?
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What is the effect of vitamin A on the activity of cytochrome P450 enzymes?
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How do inhibitors of cytochrome P450 enzymes affect the metabolism of drugs?
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What is the effect of inducers of cytochrome P450 enzymes on the metabolism of drugs?
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What is the primary factor that determines the time to reach steady state and removal time in 1st order elimination kinetics?
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What is the difference in the rate of elimination between 1st order and 0 order elimination kinetics?
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What is the consequence of small changes in dose in 0 order elimination kinetics?
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What is the equation that represents the rate of elimination of a drug?
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What is the purpose of a loading dose in drug administration?
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What is an important factor that influences enzyme activity and plasma half-life?
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What is the enzyme family involved in plasma half-life?
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What is the consequence of enzyme induction on plasma half-life?
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Study Notes
Cytochrome P450's
- Differ in amino acid sequences, leading to varying substrate specificity
- Enzyme reaction requires molecular oxygen, NADPH, and NADPH-P450 reductase to form a hydroxylated product
- ~74 CYP450 gene families, with three major families (CYP1, CYP2, CYP3) involved in drug metabolism in the liver
Factors Influencing CYP450 Activity
- Multi-allelic polymorphisms (e.g. SNPs) can change substrate binding, leading to variations in drug response
- Environmental factors:
- Smoking increases CYP450 expression, causing faster drug metabolism
- Certain diets (e.g. citrus fruits) can inhibit CYP450 activity, leading to slower metabolism
- Vitamin A enhances CYP450 activity, increasing metabolism
- Co-administration of medications can induce or inhibit CYP450, affecting drug metabolism
Phase 1 Drug Metabolism
- Occurs in the liver, but can also occur in other tissues
- Some metabolites can be more active or toxic than the parent drug
- Examples: paracetamol, prodrugs (e.g. codeine converted to morphine)
- Prodrugs are inactive until converted to their active form
- Few enzymes can catalyze the metabolism of many different drugs, leading to drug-drug interactions
Phase 2 Drug Metabolism
- Forms a conjugate with a large molecule, requiring a functional group
- In overdose, the enzyme system can become saturated, leading to toxicity (e.g. paracetamol)
Biliary Clearance of Drugs (Enterohepatic Recycling)
- Phase 2 elimination leads to conjugated drugs being eliminated into the bile ducts
- These conjugates can be cleaved off in the GIT, recycling the drug back into its active form
- Enterohepatic recycling affects the time a drug stays in the body
Plasma Half-Life and Steady State
- First-order elimination kinetics:
- Half-life is constant and independent of plasma concentration
- Rate of elimination is driven by plasma concentration (Cp)
- Constant/repeated dosing achieves a steady state
- Zero-order elimination kinetics:
- Half-life varies with plasma concentration
- Rate of elimination is independent of Cp, dependent on enzymatic turnover
- Small changes in dose can lead to disproportionate increases in plasma concentration
Dosing of Drugs
- Rate of elimination = clearance (CL) x Cp
- Loading dose: used to quickly achieve therapeutic efficacy
- Maintenance dose rate = RE or DR = CL x target Cp
Enzymes Involved in Plasma Half Life
- Metabolizing enzymes, such as CYP450, affect plasma half-life
Factors Influencing Enzyme Activity – Plasma HL
- Drug-drug interactions
- Diet
- Environmental impacts
- Polymorphisms
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Description
Learn about the characteristics and functions of Cytochrome P450 enzymes, including their substrate specificity, reaction requirements, and role in drug metabolism in the liver.
