L8 Metabolism and Drug Design

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Questions and Answers

What role does C-oxidation play in drug metabolism?

C-oxidation is involved in the dealkylation processes for various compounds, including drugs like PGE1 and Warfarin.

Why are N- and S-oxidation reactions considered more reactive?

N- and S-oxidation reactions are facilitated by electron withdrawing properties that increase their reactivity.

List two non-P450 drug metabolism pathways and their functions.

Flavin mono-oxygenase is involved in oxidations, while epoxide hydrolase assists in hydrolyses.

How does glucuronidation impact drug reactivity and size?

Glucuronidation increases both the reactivity and size of drugs, making them more water-soluble. Signup and view all the answers

What is the key difference between glucuronidation and sulphonation in drug metabolism?

Glucuronidation enhances reactivity and increases molecular size, while sulphonation primarily increases water solubility. Signup and view all the answers

Identify one intrinsic factor that affects drug metabolism and explain its impact.

Genetic polymorphism of drug metabolising enzymes affects drug metabolism by causing variability in enzyme activity among individuals. Signup and view all the answers

How does age influence drug metabolism in the body?

As individuals age, liver and heart function may decline, leading to altered drug metabolism. Signup and view all the answers

Explain why drug production cannot be a one-size-fits-all approach.

Variability in drug metabolism due to genetic and age factors necessitates a tailored approach in drug development. Signup and view all the answers

What are the key features that make an 'ideal' drug?

An 'ideal' drug should be readily absorbed after oral administration, not metabolized, have a high therapeutic efficacy, an extensive therapeutic window, and an optimal plasma half-life. Signup and view all the answers

Why is oral administration preferred over other forms despite potential challenges in drug design?

Oral administration is preferred because it has better patient compliance compared to forms like injections or suppositories. Signup and view all the answers

What is the significance of high-affinity binding in drug design?

High-affinity binding is significant because it ensures that the drug binds specifically to its pharmacodynamic target, minimizing off-target effects. Signup and view all the answers

How does drug metabolism relate to drug interactions?

Drug metabolism can lead to drug interactions as the enzymes that metabolize drugs can be influenced by other compounds, altering the drug's effectiveness or toxicity. Signup and view all the answers

What role do drug metabolizing enzymes play in drug development?

Drug metabolizing enzymes are crucial in drug development as they help to determine the metabolic pathways and potential toxicity of new chemical entities (NCEs). Signup and view all the answers

In the context of drug design, how do endogenous and exogenous compounds influence metabolism?

Both endogenous and exogenous compounds influence metabolism as cells have evolved enzymes to detoxify and process these substances, which can affect drug efficacy and safety. Signup and view all the answers

What is the implication of a drug having a long plasma half-life?

A long plasma half-life implies that the drug remains in the bloodstream for an extended period, potentially leading to cumulative exposure and toxicity if not properly managed. Signup and view all the answers

Why might a new chemical entity (NCE) be particularly susceptible to drug metabolism?

An NCE might be particularly susceptible to drug metabolism due to the presence of various endogenous enzymes that target foreign substances for detoxification. Signup and view all the answers

What role do cytochrome P450 isoforms play in drug metabolism?

Cytochrome P450 isoforms are responsible for more than 90% of xenobiotic oxidation reactions. Signup and view all the answers

How does the presence of an OH group in a drug like paracetamol affect its metabolism?

A drug with an OH group can proceed directly to conjugation and may not require conjugation if it is sufficiently soluble. Signup and view all the answers

What are the main types of reactions involved in phase 1 drug metabolism?

The main reactions include oxidation, reduction, and nucleophilic trapping processes. Signup and view all the answers

Describe the significance of glutathione in drug metabolism.

Glutathione protects against free radicals through nucleophilic trapping processes. Signup and view all the answers

In which cellular compartment are cytochrome P450 enzymes primarily located?

Cytochrome P450 enzymes are primarily located in the smooth endoplasmic reticulum. Signup and view all the answers

What is the significance of cytochrome P450 reductase in drug metabolism?

Cytochrome P450 reductase provides the necessary electrons for the catalytic cycles of cytochrome P450 enzymes. Signup and view all the answers

What are the cofactors involved in the conjugation reactions of drugs?

Cofactors like PAPS, acetyl coenzyme A, UDP-glucuronic acid, and S-adenosylmethionine are involved in conjugation. Signup and view all the answers

What is the common characteristic of the superfamily of cytochrome P450 proteins?

They are haem-thiolate proteins that exist in multiple isoforms. Signup and view all the answers

What metabolic phenotype predominates in Africans for CYP2C8?

*2 Signup and view all the answers

Which CYP polymorphism is more prevalent among Caucasians for CYP2C9?

*3 Signup and view all the answers

What is the most common syndrome related to glucuronidation polymorphisms and its characteristic?

Gilbert's syndrome; mild bilirubin glucuronidation deficiency. Signup and view all the answers

What happens to renal function and drug metabolism in the elderly?

Renal function declines, leading to decreased drug excretion. Signup and view all the answers

How does aging affect liver blood flow and its significance for drug metabolism?

Liver blood flow decreases by 0.5-1.5% per year, impacting metabolism capacity. Signup and view all the answers

What genetic variations are significant for the ultra rapid metabolizer phenotype associated with?

Polymorphisms in Phase 2 - UGTs. Signup and view all the answers

What are the implications of bilirubin buildup in relation to Gilbert's syndrome?

Bilirubin buildup causes jaundice; UV treatment helps break it down. Signup and view all the answers

Which ethnic group shows a higher incidence of 2 and 3 polymorphisms of CYP2C19?

Africans Signup and view all the answers

What is the significance of CYP activity in neonates compared to adults?

Neonates exhibit 30-50% CYP activity of adults, which affects drug metabolism and clearance. Signup and view all the answers

How does the maturation of drug metabolism pathways occur from infancy to early childhood?

Phase I and Phase II metabolic pathways reach maturity around 2 to 3 years of age. Signup and view all the answers

What role does UGT1A1 play in neonates and how is it related to jaundice?

UGT1A1 is activated 24 hours after birth and plays a crucial role in bilirubin metabolism, contributing to jaundice in neonates. Signup and view all the answers

Why are prodrugs beneficial in drug design, particularly for neonates?

Prodrugs enhance drug permeability and are converted into the active form within the body, improving therapeutic effects in neonates. Signup and view all the answers

How does L-DOPA function as a prodrug and what transport mechanisms are involved?

L-DOPA has an amino acid group that allows it to be taken up by amino acid transporters at the blood-brain barrier, where it is converted to dopamine. Signup and view all the answers

What are the metabolic characteristics of glutathione conjugation in neonates?

Neonates are more efficient at glutathione conjugation than adults, as they rely less on mitochondrial metabolism. Signup and view all the answers

Discuss the differences in renal clearance between premature and full-term neonates.

Premature babies exhibit reduced renal clearance compared to full-term neonates, affecting drug excretion. Signup and view all the answers

Name two examples of prodrugs and describe their clinical applications.

Enalapril is an ACE inhibitor that improves oral availability, while Xeloda is an anti-cancer agent with reduced toxicity. Signup and view all the answers

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Study Notes

Metabolism Overview

Metabolism is regulated and influences how drugs are designed to avoid drug interactions.
Drug metabolising enzymes play a crucial role in ensuring effective drug action and minimizing adverse effects.

Characteristics of an “Ideal” Drug

Readily absorbed post-oral administration, enhancing compliance.
Not metabolised to ensure sustained therapeutic effect.
High-affinity binding at a single pharmacodynamic target.
High therapeutic efficacy with an extensive therapeutic window.
Optimal plasma half-life: long enough for effect, short enough to prevent toxicity.

Drug Administration Preferences

Oral administration preferred for better patient compliance over other forms (e.g., suppository, injection).
Specific binding reduces off-target effects, minimizing toxicity linked to drug exposure.

Drug Metabolism and Its Necessity

New Chemical Entities (NCEs) undergo metabolism due to enzymes evolved for processing both endogenous and exogenous compounds.
Metabolism is essential for detoxifying substances from diet and environment.

Drug Metabolising Enzymes Classification

Oxidations: Predominantly via Cytochrome P450, flavin mono-oxygenase, and alcohol dehydrogenase.
Reductions: Limited processes like nitro- and azo-reductions.
Conjugations: Involves cofactor addition during drug processing for elimination.
Nucleophilic Trapping: GSH reacts with electrophilic xenobiotics, forming protective adducts.

Cytochrome P450 Enzymes

A superfamily of enzymes (40-65 kDa) responsible for over 90% of xenobiotic oxidation reactions.
Expressed mainly in the liver, followed by GIT, kidneys, lungs, and skin.
Functions best in the smooth endoplasmic reticulum with cytochrome P450 reductase aiding the catalytic cycle.

Phase 1 and Phase 2 Metabolism

Phase 1: Mainly oxidation reactions (>95% via Cytochrome P450).
Phase 2: Conjugation reactions such as glucuronidation and sulphation enhance solubility and reactivity of drugs.

Factors Influencing Drug Metabolism

Intrinsic factors include genetic polymorphisms, age, and ethnicity, affecting enzyme activity.
Age impacts liver and renal function, altering drug dosage requirements.

Ethnic Variations in Metabolism

Genetic variants like CYP2C8 and CYP2C9 show different prevalence across ethnic groups, affecting drug metabolism.
Specific polymorphisms conferring selective advantages have been identified.

Geriatric patients may experience various declines in liver and renal function, necessitating adjusted dosages.
Neonates have reduced CYP activity; drug half-lives can be extended significantly.

Pro-drug Design Benefits

Pro-drugs enhance permeability and are converted to active forms within cells.
Examples include L-DOPA, which crosses the blood-brain barrier and is converted to dopamine.

Notable Pro-drug Examples

Enalapril: Improves oral availability as an ACE inhibitor.
Dipivefrin: Enhances corneal permeability for glaucoma treatment.
Xeloda: Anti-cancer agent with reduced toxicity and high tumour selectivity.

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