A 58-year-old man with hypertension and type 2 diabetes is on amlodipine, metformin, and atorvastatin. He develops a urinary tract infection and is prescribed trimethoprim-sulfamethoxazole (TMP-SMX). Which of the following drug interactions is NOT likely to occur with TMP-SMX in this patient?

Question

Accepted Answer

D. Increased amlodipine levels with risk of hypotension. ## Drug Interaction Analysis: TMP-SMX

**Key Point:** TMP-SMX is a potent inhibitor of renal tubular secretion and hepatic metabolism (CYP3A4, CYP2C9), but it does NOT significantly inhibit CYP3A4-mediated metabolism of amlodipine.

### Mechanism of TMP-SMX Interactions

| Drug | Mechanism of Interaction | Clinical Consequence |
|------|--------------------------|----------------------|
| Metformin | Reduces renal clearance via tubular secretion inhibition | ↑ Metformin levels → lactic acidosis risk |
| Warfarin | Inhibits CYP2C9 metabolism | ↑ INR → bleeding risk |
| Atorvastatin | Inhibits CYP3A4 metabolism | ↑ Statin levels → myopathy, rhabdomyolysis |
| Amlodipine | Minimal CYP3A4 inhibition by TMP-SMX | No clinically significant interaction |

**High-Yield:** TMP-SMX is a broad-spectrum inhibitor of drug metabolism and renal secretion. Its major interactions involve:
1. **Renal tubular secretion inhibition** → affects metformin, trimethoprim itself, cimetidine
2. **CYP2C9 inhibition** → affects warfarin, NSAIDs, sulfonylureas
3. **CYP3A4 inhibition** → affects atorvastatin, but NOT amlodipine (which is metabolized by CYP3A4 but not significantly affected by TMP-SMX at therapeutic doses)

**Clinical Pearl:** While amlodipine IS metabolized by CYP3A4, TMP-SMX is a weak inhibitor of this enzyme in clinical practice. Potent CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin) cause significant amlodipine interactions; TMP-SMX does not.

### Why Each Interaction Occurs

**Metformin:** TMP-SMX inhibits organic cation transporter (OCT2) and reduces glomerular filtration, decreasing metformin clearance. Risk of lactic acidosis increases.

**Warfarin:** TMP-SMX displaces warfarin from protein binding and inhibits CYP2C9. INR rises significantly.

**Atorvastatin:** TMP-SMX inhibits CYP3A4, increasing statin concentration and myopathy risk.

**Amlodipine:** Although amlodipine undergoes CYP3A4 metabolism, TMP-SMX does not produce clinically meaningful inhibition at standard doses. This is the exception among the listed interactions.

Answer

A. Reduced anticoagulant effect of warfarin (if patient were on it)

Answer

B. Increased atorvastatin levels leading to myopathy risk

Answer

C. Increased serum creatinine and reduced renal clearance of metformin

A 58-year-old man with hypertension and type 2 diabetes is on amlodipine, metformin, and atorvastatin. He develops a urinary tract infection and is prescribed trimethoprim-sulfamethoxazole (TMP-SMX). Which of the following drug interactions is NOT likely to occur with TMP-SMX in this patient?

Explanation

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