4.2: Drug Metabolism & Elimination Pathways

4.2: Drug Metabolism & Elimination Pathways

Elimination is the irreversible removal of drug from the body and is the sum of two distinct processes: metabolism (biotransformation) and excretion. Lipophilic drugs must be converted into hydrophilic metabolites to prevent renal reabsorption and facilitate excretion.

Phase I and Phase II Metabolism

Drug metabolism occurs primarily in the liver, catalyzed by enzymes located in the smooth endoplasmic reticulum (microsomes) or cytosol.

Phase I: Functionalisation Reactions

Phase I reactions introduce or expose a functional group (e.g., $-\text{OH}$, $-\text{NH}_2$, $-\text{SH}$, $-\text{COOH}$) on the drug molecule. These reactions include oxidation, reduction, and hydrolysis.

• Purpose: To slightly increase the drug's hydrophilicity and, more importantly, prepare the molecule for conjugation in Phase II. Phase I metabolites can be pharmacologically active, inactive, or toxic.

The Cytochrome P450 (CYP) Superfamily

The CYP enzymes are haem-containing proteins responsible for the oxidation of the majority of clinical drugs.

• CYP3A4: The most abundant CYP enzyme in the liver and gut wall. It metabolizes approximately $50%$ of all clinical drugs.
  • Substrates: Simvastatin, atorvastatin, amlodipine, felodipine, verapamil, sildenafil, cyclosporin, tacrolimus, midazolam.
  • Inhibitors: Grapefruit juice (selectively inhibits gut CYP3A4), clarithromycin, erythromycin, ketoconazole, itraconazole, ritonavir, amiodarone.
  • Inducers: Rifampicin, carbamazepine, phenytoin, phenobarbitone, St John's Wort.
• CYP2D6: Notable for significant genetic polymorphism. It exhibits a high density of mutations that lead to four phenotypes: Poor Metabolisers (PM), Intermediate Metabolisers (IM), Extensive Metabolisers (EM), and Ultra-rapid Metabolisers (UM).
  • Substrates: Codeine, tramadol, metoprolol, amitriptyline, venlafaxine, tamoxifen.
  • Inhibitors: Fluoxetine, paroxetine, bupropion.
  • Clinical Case: Codeine is a prodrug that must be activated via $O$-demethylation by CYP2D6 to form morphine. PMs (~7–10% of Caucasians) get virtually no pain relief from codeine. EMs and UMs convert codeine rapidly. In a UM (~5–10% of some populations), a standard dose of codeine can lead to toxic, life-threatening morphine levels. In Australia, codeine is contraindicated in patients under 12 years of age, pediatric patients post-tonsillectomy/adenoidectomy, and breastfeeding mothers due to the fatal risk of morphine toxicity.
• CYP2C9:
  • Substrates: S-warfarin (active enantiomer), phenytoin, sulfonylureas (gliclazide), NSAIDs (ibuprofen, celecoxib).
  • Inhibitors: Amiodarone, fluconazole, miconazole (including oral gel - a high-yield OTC counseling interaction that causes severe INR spikes and hemorrhage in warfarin patients), sulfamethoxazole/trimethoprim (Bactrim), metronidazole.
  • Inducers: Rifampicin, carbamazepine.
• CYP2C19:
  • Substrates: Clopidogrel (prodrug requiring activation), omeprazole, esomeprazole, citalopram, diazepam.
  • Inhibitors: Omeprazole, esomeprazole.
  • Clinical Interaction: Co-prescribing omeprazole or esomeprazole with clopidogrel is avoided. These PPIs inhibit CYP2C19, preventing the activation of clopidogrel, leading to increased risk of myocardial infarction or stent thrombosis. Pantoprazole or rabeprazole are preferred PPI alternatives due to lower CYP2C19 inhibition.

Non-CYP Phase I Metabolism

• Esterases: Hydrolyze esters (e.g., aspirin is hydrolyzed by esterases in the blood and liver to active salicylic acid).
• Alcohol Dehydrogenase (ADH) and Aldehyde Dehydrogenase (ALDH): Oxidize ethanol to acetaldehyde, and then to acetate. Disulfiram inhibits ALDH, causing acetaldehyde accumulation (disulfiram reaction: severe flushing, vomiting, tachycardia). Metronidazole, tinidazole, and sulfonylureas can trigger a similar reaction.

Phase II: Conjugation Reactions

Phase II reactions couple the parent drug or its Phase I metabolite with an endogenous polar molecule (e.g., glucuronic acid, sulfate, glycine, glutathione, acetate, methyl groups) to form highly water-soluble, inactive conjugates.

• Glucuronidation (UGT): The most common Phase II reaction.
  • Morphine: Metabolized by UGT2B7 to Morphine-3-Glucuronide (M3G, inactive but neurotoxic, causing myoclonus and seizures in renal impairment) and Morphine-6-Glucuronide (M6G, an active analgesic, twice as potent as morphine, which accumulates in renal failure and causes respiratory depression).
• Acetylation (NAT): NAT2 exhibits genetic polymorphism, dividing populations into fast and slow acetylators. Slow acetylators are at high risk of toxicity and adverse events from drugs like:
  • Isoniazid: Causes peripheral neuropathy (mitigated by co-prescribing pyridoxine/vitamin B6).
  • Hydralazine, Procainamide: Can cause drug-induced lupus erythematosus (DILE).
• Glutathione (GSH) Conjugation: Crucial for paracetamol detoxification.
  • Paracetamol Metabolism: At therapeutic doses, $90%$ is conjugated via glucuronidation and sulfation. The remaining $5-10%$ is oxidized by CYP2E1/CYP3A4/CYP1A2 to a highly reactive hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is immediately detoxified by conjugation with intracellular glutathione (GSH).
  • Paracetamol Overdose: Glucuronidation and sulfation pathways saturate. A larger fraction is shunted to CYP pathway, producing excess NAPQI. Once liver glutathione stores are depleted by $>70%$, free NAPQI covalently binds to hepatic cellular macromolecules, causing acute liver necrosis. Acetylcysteine (NAC) acts as a glutathione precursor and substitute, restoring hepatic detoxifying capacity if administered early.

Enterohepatic Recirculation

Some glucuronide conjugates are excreted into the bile and enter the small intestine. Gut bacteria express $\beta$-glucuronidase, which hydrolyzes the conjugate, releasing the parent lipophilic drug. The drug is then reabsorbed into the portal vein and returned to the liver. This extends the drug's half-life (e.g., morphine, ethinylestradiol).

• Clinical Myth: Broad-spectrum antibiotics (e.g., amoxicillin) were thought to kill gut bacteria, reduce enterohepatic recirculation, and lead to oral contraceptive failure. Current Australian guidelines (AMH, eTG complete) state that additional contraceptive precautions are not routinely required when using non-enzyme inducing antibiotics with oral contraceptives, unless diarrhea or vomiting occurs.

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Renal Excretion

The kidney is the primary organ for drug excretion. Renal elimination is the net result of three processes:

$\text{Renal Excretion} = \text{Glomerular Filtration} + \text{Active Tubular Secretion} - \text{Passive Tubular Reabsorption}$

1. Glomerular Filtration

• Occurs in the glomerulus. Only free (unbound) drug dissolved in plasma water is filtered.
• Highly protein-bound drugs (e.g., warfarin) are not filtered.
• Filtration rate depends on the Glomerular Filtration Rate (GFR $\approx 120 \text{ mL/min}$).

2. Active Tubular Secretion

• Occurs in the proximal tubule. It is a carrier-mediated, energy-dependent process that can secrete both free and protein-bound drug.
• Driven by organic anion transporters (OATs, for acidic drugs like penicillins, methotrexate, NSAIDs, loop diuretics) and organic cation transporters (OCTs, for basic drugs like metformin, cimetidine).
• Drug Interactions:
  • Probenecid competes with penicillins for OAT-mediated secretion, raising penicillin levels and prolonging its half-life (used to therapeutic advantage in neurosyphilis).
  • NSAIDs (e.g., ibuprofen) inhibit the renal secretion of methotrexate by competing for OAT. This causes methotrexate accumulation and life-threatening myelosuppression, mucositis, and acute kidney injury.

3. Passive Tubular Reabsorption

• Occurs along the renal tubule (especially distal tubule).
• Highly lipophilic and non-ionized drugs are passively reabsorbed back into the bloodstream, while ionized, hydrophilic drugs are trapped in the urine and excreted.
• Ion Trapping: Urine pH can be manipulated to change the ionization state of drugs that are weak acids or bases, altering their excretion.
  • Weak Acids (e.g., Salicylates/Aspirin, Phenobarbitone): $\text{pH} = \text{p}K_a + \log\left(\frac{[A^-]}{[HA]}\right)$ Alkalinisation of the urine (using IV sodium bicarbonate to raise urine pH to 7.5–8.5) shifts the equilibrium towards the ionized carboxylate form ($A^-$). The ionized molecule cannot cross the lipid tubular membrane, is 'trapped' in the urine, and is excreted. This is standard therapy in moderate-to-severe salicylate poisoning.
  • Weak Bases (e.g., Amphetamines): Acidification of the urine (using ammonium chloride) traps weak bases ($BH^+$) in the urine. However, this is rarely performed clinically due to the risk of systemic metabolic acidosis.

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Biliary Excretion

Biliary excretion is the active secretion of drugs or their metabolites from hepatocytes into the bile, which is then emptied into the duodenum.

• Mechanism: Mediated by active transporters on the canalicular membrane, including P-glycoprotein, breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2).
• Characteristics: Favors large, polar molecules, typically with a molecular weight $>300-500 \text{ Da}$, and glucuronide conjugates (e.g., ceftriaxone, erythromycin, atorvastatin).
• Excretion: Ultimately eliminated via the faeces, unless enterohepatic recirculation occurs.