Drug Metabolism — MCQs
Which antiepileptic drug requires regular monitoring of liver enzymes?
What is the mechanism of metabolism for alcohol, aspirin, and phenytoin at high doses?
A factor that is likely to increase the duration of action of a drug that is partially metabolized by CYP3A4 in the liver is:
Phase 1 biotransformation includes
Administration of which of the following drugs would increase the bioavailability of saquinavir?
Glucuronide reaction is seen in
A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?
Bile salts undergo conjugation for enhanced solubility:
All of the following are true about glutathione, except:
In the liver, what is ethanol primarily converted to?
Drug Metabolism Indian Medical PG Practice Questions and MCQs
Question 1: Which antiepileptic drug requires regular monitoring of liver enzymes?
- A. Valproate (Correct Answer)
- B. Levetiracetam
- C. Lamotrigine
- D. Phenytoin
Explanation: ***Valproate*** - **Valproate** is known to cause dose-related **hepatotoxicity**, ranging from asymptomatic enzyme elevation to fatal hepatic failure, especially in young children and those on polytherapy. - Regular monitoring of **liver function tests (LFTs)** is crucial to detect early signs of liver injury and adjust treatment. *Levetiracetam* - **Levetiracetam** is generally well-tolerated and does not typically require routine monitoring of liver enzymes due to its primary renal excretion and low potential for hepatotoxicity. - While mild, transient elevations in LFTs can occur, they are usually not clinically significant. *Lamotrigine* - **Lamotrigine** is primarily known for causing serious **skin rashes** (e.g., Stevens-Johnson syndrome) rather than significant hepatotoxicity. - Routine liver enzyme monitoring is generally not recommended unless there are other risk factors for hepatic dysfunction. *Phenytoin* - Although **phenytoin** can cause idiosyncratic liver injury, it is not as consistently associated with dose-related hepatotoxicity as valproate. - Monitoring of **phenytoin levels** is crucial [1], but routine liver enzyme monitoring is not typically mandated as strictly as for valproate.
Question 2: What is the mechanism of metabolism for alcohol, aspirin, and phenytoin at high doses?
- A. First pass kinetics
- B. First order kinetics
- C. Zero order kinetics (Correct Answer)
- D. Second order kinetics
Explanation: ***Zero order kinetics*** - This mechanism occurs when the **metabolic enzymes become saturated at high drug concentrations**, leading to a constant amount (not a constant percentage) of drug being eliminated per unit time. - Alcohol, aspirin, and phenytoin are examples of drugs that exhibit **saturable metabolism**, transitioning from first-order to zero-order kinetics at higher doses. *First pass kinetics* - This describes the **metabolism of a drug by the liver or gut wall enzymes before it reaches systemic circulation** after oral administration. - While relevant to the oral bioavailability of these drugs, it does not describe the specific mechanism of elimination at high doses. *First order kinetics* - In this mechanism, a **constant fraction or percentage of the drug is eliminated per unit of time**, meaning the rate of elimination is directly proportional to the drug concentration. - Most drugs follow first-order kinetics at therapeutic doses because metabolizing enzymes are not saturated. *Second order kinetics* - This is a **less common pharmacokinetic model** where the rate of elimination is proportional to the square of the drug concentration or involves two reactants. - It does not typically describe the common elimination patterns of most drugs, including alcohol, aspirin, and phenytoin.
Question 3: A factor that is likely to increase the duration of action of a drug that is partially metabolized by CYP3A4 in the liver is:
- A. Chronic administration of phenobarbital with the drug
- B. Displacement from tissue binding sites by another drug
- C. Chronic administration of rifampicin
- D. Chronic administration of cimetidine with the drug (Correct Answer)
Explanation: ***Chronic administration of cimetidine with the drug*** - **Cimetidine** is a potent inhibitor of various **cytochrome P450 (CYP450) enzymes**, including **CYP3A4**. - By inhibiting the metabolism of a drug predominantly metabolized by **CYP3A4**, cimetidine will increase its plasma concentration and extend its **duration of action**. *Chronic administration of phenobarbital with the drug* - **Phenobarbital** is a strong **inducer of CYP450 enzymes**, including **CYP3A4**. - Induction would accelerate the metabolism of the drug, thus **decreasing its duration of action**, not increasing it. *Displacement from tissue binding sites by another drug* - Displacement from tissue binding sites would primarily increase the **free fraction of the drug in the plasma**, leading to a more rapid distribution to eliminating organs and potentially **shorter duration of action** if elimination is extraction-limited. - This mechanism does not directly impact the **metabolic rate** unless clearance is significantly altered through increased availability for metabolism. *Chronic administration of rifampicin* - **Rifampicin** is a potent **inducer of CYP3A4** and other CYP enzymes. - Its administration would lead to **increased metabolism** of the co-administered drug, thereby **reducing its duration of action**.
Question 4: Phase 1 biotransformation includes
- A. Reduction (Correct Answer)
- B. Methylation
- C. Acetylation
- D. Sulfate conjugation
Explanation: ***Reduction*** - **Phase 1 biotransformation reactions** are non-synthetic reactions that introduce or expose polar functional groups (e.g., -OH, -NH2, -SH) on xenobiotics to make them more water-soluble. - The three main Phase 1 reactions are **oxidation**, **reduction**, and **hydrolysis**. - These reactions typically involve **cytochrome P450 enzymes** and prepare drugs for excretion or Phase 2 conjugation. *Acetylation* - **Acetylation** is a **Phase 2 (conjugation) reaction**, not Phase 1. - Involves transfer of an acetyl group to amine-containing drugs via **N-acetyltransferase**. - Increases water solubility and facilitates excretion. *Sulfate conjugation* - **Sulfate conjugation** is a **Phase 2 (conjugation) reaction**, not Phase 1. - Involves addition of a sulfate group via **sulfotransferase enzymes**. - Significantly increases hydrophilicity for renal excretion. *Methylation* - **Methylation** is a **Phase 2 (conjugation) reaction**, not Phase 1. - Involves addition of a methyl group via **methyltransferase enzymes**. - Unlike most Phase 2 reactions, methylation may sometimes **decrease** water solubility but is still classified as conjugation.
Question 5: Administration of which of the following drugs would increase the bioavailability of saquinavir?
- A. Cimetidine
- B. Vitamin C
- C. Ritonavir (Correct Answer)
- D. Ganciclovir
Explanation: **Ritonavir** - **Ritonavir** is a potent **CYP3A4 inhibitor**, which is the primary enzyme responsible for the metabolism of saquinavir. - By inhibiting **saquinavir** metabolism, ritonavir significantly **increases its plasma concentrations and bioavailability**, making it an effective pharmacokinetic enhancer. - This combination (saquinavir/ritonavir) is a clinically established strategy in antiretroviral therapy. *Cimetidine* - **Cimetidine** inhibits various cytochrome P450 enzymes but is a less potent and more general inhibitor compared to ritonavir, particularly for **CYP3A4**. - While it could theoretically have some effect on drug metabolism, its impact on saquinavir's bioavailability would be **clinically insignificant** compared to ritonavir. *Vitamin C* - **Vitamin C** (ascorbic acid) is an antioxidant and plays various roles in the body. - It has **no significant interaction** with cytochrome P450 enzymes and would not affect the metabolism or bioavailability of saquinavir. *Ganciclovir* - **Ganciclovir** is an antiviral drug primarily used to treat cytomegalovirus (CMV) infections. - It does not significantly inhibit or induce cytochrome P450 enzymes and would therefore **not affect the bioavailability** of saquinavir.
Question 6: Glucuronide reaction is seen in
- A. Phase 2 (Correct Answer)
- B. NADPH-dependent reaction
- C. Phase 1
- D. Non enzymatic reaction
Explanation: ***Phase 2*** - **Glucuronide conjugation** is a prominent **Phase 2 biotransformation reaction** where glucuronic acid is added to a drug or metabolite. - This reaction increases the **water solubility** of xenobiotics, facilitating their excretion from the body. - Catalyzed by **UDP-glucuronosyltransferase (UGT)** enzymes using **UDP-glucuronic acid** as the donor molecule. *NADPH-dependent reaction* - **Glucuronidation does not require NADPH** as a cofactor. - **NADPH** is primarily involved in **Phase 1 reactions** catalyzed by cytochrome P450 enzymes for oxidation and reduction reactions. - The glucuronidation reaction uses **UDP-glucuronic acid**, not NADPH, as the source of the glucuronic acid moiety. *Phase 1* - **Phase 1 reactions** typically involve **oxidation**, **reduction**, or **hydrolysis**, introducing or unmasking functional groups (e.g., -OH, -SH, -NH2). - These reactions aim to make the parent compound more polar and often serve as a prelude to Phase 2 reactions. - Glucuronidation is a Phase 2 conjugation reaction, not Phase 1. *Non enzymatic reaction* - **Glucuronidation** is a highly specific **enzymatic reaction** catalyzed by UDP-glucuronosyltransferase (UGT) enzymes. - **Non-enzymatic reactions** in drug metabolism are less common and typically involve spontaneous degradation or chemical rearrangements without enzyme involvement.
Question 7: A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?
- A. Isoniazid
- B. Amiodarone
- C. Carbamazepine (Correct Answer)
- D. Cimetidine
Explanation: ***Carbamazepine*** - Carbamazepine **induces cytochrome P450 enzymes**, specifically **CYP3A4** and **CYP2C9**, which are responsible for warfarin metabolism. - This induction leads to a **faster metabolism of warfarin**, thus **decreasing its anticoagulant effect** and thereby reducing the risk of bleeding. *Isoniazid* - Isoniazid is an **inhibitor of cytochrome P450 enzymes**, primarily **CYP2C9**, which metabolizes the more potent S-warfarin isomer. - This inhibition **decreases warfarin metabolism**, leading to **increased anticoagulant effect** and higher risk of bleeding. *Amiodarone* - Amiodarone is a potent **inhibitor of cytochrome P450 enzymes**, significantly **CYP2C9** and **CYP3A4**. - It leads to a **reduced metabolism of warfarin**, causing **elevated INR** and an increased risk of bleeding. *Cimetidine* - Cimetidine is a known **inhibitor of various cytochrome P450 enzymes**, particularly **CYP1A2**, **CYP2C9**, and **CYP3A4**. - Its inhibitory action on warfarin metabolism results in **higher warfarin levels** and an **increased risk of bleeding**.
Question 8: Bile salts undergo conjugation for enhanced solubility:
- A. After conjugation with derived proteins
- B. After conjugation with lysine
- C. After conjugation with taurine and glycine (Correct Answer)
- D. After conjugation with betaglucuronic acid
Explanation: ***After conjugation with taurine and glycine*** - This statement accurately describes the most common conjugation pathway for bile acids, increasing their **amphipathic properties** and solubility. - Conjugation with these amino acids forms **bile salts** (e.g., glycocholate, taurocholate), which are essential for **micelle formation** and fat digestion. - This is the primary mechanism by which bile acids become bile salts with enhanced solubility. *After conjugation with betaglucuronic acid* - While bile acids do undergo conjugation for increased solubility, they are primarily conjugated with glycine or taurine, not beta-glucuronic acid. - Conjugation with beta-glucuronic acid is a common detoxification pathway for many xenobiotics and bilirubin, but not the primary method for bile acids. *After conjugation with derived proteins* - Bile salts are primarily steroid derivatives and are not conjugated with derived proteins. - The purpose of conjugation is to increase hydrophilicity, which proteins would not achieve in this context. *After conjugation with lysine* - Lysine is an amino acid but is not involved in the conjugation of bile acids. - Bile acid conjugation specifically uses the amino acids glycine and taurine.
Question 9: All of the following are true about glutathione, except:
- A. It is co-factor of various enzymes
- B. It converts hemoglobin to methemoglobin (Correct Answer)
- C. It is a tripeptide
- D. It conjugates xenobiotics
Explanation: ***It converts hemoglobin to methemoglobin*** - Glutathione is a **reducing agent** that helps protect hemoglobin from oxidation, thus **preventing** the formation of methemoglobin. - **Methemoglobin** occurs when the iron in hemoglobin is oxidized from the ferrous (Fe2+) to the ferric (Fe3+) state, which is a process glutathione actively counters. *It is co-factor of various enzymes* - Glutathione serves as a crucial **co-factor** for several enzymes, including **glutathione peroxidase**, which plays a vital role in antioxidant defense. - It participates in various **detoxification reactions** and catalyzes the reduction of harmful reactive oxygen species. *It is a tripeptide* - Glutathione is indeed a **tripeptide** composed of three amino acids: **glutamate**, **cysteine**, and **glycine**. - Its unique structure enables its diverse biological functions, including its prominent role as an antioxidant. *It conjugates xenobiotics* - Glutathione plays a critical role in **detoxifying xenobiotics** (foreign compounds) by conjugating with them, making them more water-soluble and easier to excrete. - This process is mediated by **glutathione S-transferases**, which attach glutathione to various toxic compounds.
Question 10: In the liver, what is ethanol primarily converted to?
- A. Methanol
- B. Pyruvate
- C. Acetaldehyde (Correct Answer)
- D. Oxaloacetate
Explanation: **Explanation:** The metabolism of ethanol primarily occurs in the liver through a series of oxidative reactions. The first and rate-limiting step involves the conversion of **ethanol to acetaldehyde**. This reaction is catalyzed by the cytosolic enzyme **Alcohol Dehydrogenase (ADH)**, which utilizes $NAD^+$ as a co-factor, reducing it to $NADH$. Acetaldehyde is a highly reactive and toxic intermediate responsible for many of the adverse effects of alcohol consumption (e.g., nausea, tachycardia). It is subsequently converted to acetate by Mitochondrial Aldehyde Dehydrogenase (ALDH2). **Analysis of Incorrect Options:** * **Methanol (A):** Methanol is a different type of alcohol (wood alcohol). It is not a metabolite of ethanol; rather, it is metabolized by the same enzyme system into toxic formaldehyde and formic acid. * **Pyruvate (B):** Pyruvate is the end-product of glycolysis. While ethanol metabolism increases the $NADH/NAD^+$ ratio, this actually shifts the equilibrium *away* from pyruvate, converting it into lactate instead (leading to lactic acidosis). * **Oxaloacetate (D):** Oxaloacetate is an intermediate of the TCA cycle and gluconeogenesis. High levels of $NADH$ from ethanol metabolism cause oxaloacetate to be diverted to malate, contributing to the inhibition of gluconeogenesis and subsequent fasting hypoglycemia. **High-Yield Clinical Pearls for NEET-PG:** 1. **Disulfiram (Antabuse):** Inhibits **Aldehyde Dehydrogenase**, causing acetaldehyde accumulation. This leads to the "Disulfiram-like reaction" (flushing, vomiting), used as a deterrent in chronic alcoholism. 2. **Fomepizole:** Inhibits **Alcohol Dehydrogenase**; it is the preferred antidote for methanol or ethylene glycol poisoning. 3. **Metabolic Derangements:** Ethanol metabolism increases the $NADH/NAD^+$ ratio, leading to hypoglycemia, lactic acidosis, and fatty liver (steatosis) due to increased fatty acid synthesis.
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