**Question:** All the following drugs undergo metabolism by acetylation EXCEPT

A. Acetaminophen
B. Aspirin
C. Naproxen
D. Codeine

**Core Concept:**
Acetylation is a process of conjugation in drug biotransformation, where a drug molecule is covalently bonded with acetyl group. This process helps in the clearance of drugs from the body and also plays a role in drug-drug interactions. Acetylation is catalyzed by various enzymes, primarily N-acetyl-transpeptidase (NAD).

**Why the Correct Answer is Right:**
The correct answer is D, "Codeine." Codeine is an opioid analgesic and is a prodrug, meaning it is not active in its original form and requires conversion to its active form, namely, morphine, which is responsible for its analgesic effects. Unlike other drugs in the list, codeine is not directly acetylated to form morphine, as morphine itself is already an active molecule. This distinction is crucial because acetylation process is essential for the activation of drugs like Acetaminophen (Paracetamol), Aspirin, and Naproxen.

**Why Each Wrong Option is Incorrect:**
A. Acetaminophen (Paracetamol) undergoes acetylation to form its active form, p-aminophenol, which contributes to its analgesic and antipyretic effects.
B. Aspirin (Salicylic Acid) is converted into its active form, Salicylic Acid, which is responsible for its analgesic, antipyretic, and anti-inflammatory effects. This process involves acetylation.
C. Naproxen (p-methoxybenzoic acid) is converted into its active form, Naproxen Sodium, which is responsible for its analgesic, anti-inflammatory, and antipyretic effects. Acetylation is involved in this conversion process.

**Codeine:** Unlike the other drugs, codeine is not directly acetylated to form morphine, which is responsible for its analgesic effects. Codeine is converted to morphine through a series of hydroxylation and demethylation reactions, followed by reductive N-demethylation. These reactions occur in the liver.

**Clinical Pearl:**
Understanding the biotransformation pathways of drugs is crucial for safe prescribing practice and predicting drug-drug interactions. For example, acetaminophen (Paracetamol) can cause severe liver injury when taken in high doses, as it undergoes acetylation to form reactive intermediates, which can lead to oxidative stress and hepatotoxicity.

**Why Codeine is Not Acetylated:** Codeine is an opioid analgesic that requires multiple enzymatic conversions before its active form, morphine, is formed. These conversions involve hydroxylation, demethylation, and reductive N-demethylation. The active form, morphine, is responsible for its analgesic effects. Unlike other drugs, codeine is not directly acetylated to form morphine. Instead, it undergoes a series of conversions before morphine is formed