A 52-year-old man with autoimmune hepatitis is started on azathioprine 50 mg daily alongside prednisolone. At 3 weeks, he develops fever, sore throat, and a white blood cell count of 2,100/μL (neutrophils 45%). His liver function tests show ALT 85 U/L (baseline 120 U/L). The patient reports taking allopurinol 300 mg daily for asymptomatic hyperuricemia. Which drug interaction is most likely responsible for his bone marrow suppression, and what is the underlying mechanism?

Explanation

## Azathioprine–Allopurinol Interaction **Key Point:** Azathioprine + allopurinol is a **contraindicated combination** due to a critical drug interaction that can cause severe bone marrow suppression. ### Mechanism of the Interaction **Azathioprine metabolism pathway:** ```mermaid flowchart LR A[Azathioprine]:::outcome --> B[6-mercaptopurine]:::outcome B --> C[Xanthine oxidase]:::action C --> D[Inactive metabolites]:::outcome E[Allopurinol]:::action -->|Inhibits| C C -->|Normal pathway| D C -->|With allopurinol| F[Accumulation of 6-MP]:::urgent F --> G[Severe myelosuppression]:::urgent ``` 1. **Azathioprine** is a prodrug converted to **6-mercaptopurine (6-MP)** 2. **6-MP is metabolized by xanthine oxidase** to inactive metabolites 3. **Allopurinol inhibits xanthine oxidase** (its therapeutic action for gout) 4. **Result:** 6-MP accumulates → **5–10-fold increase in 6-MP levels** 5. **Consequence:** Severe myelosuppression, leukopenia, thrombocytopenia, anemia ### Clinical Presentation in This Case | Finding | Explanation | |---------|-------------| | WBC 2,100/μL | Severe leukopenia from 6-MP accumulation | | Neutrophils 45% | Selective neutropenia (6-MP toxicity) | | Fever + sore throat | Neutropenic infection risk | | ALT improving (120 → 85) | Autoimmune hepatitis responding to therapy; marrow suppression is drug toxicity, not disease | | Onset at 3 weeks | Time for 6-MP levels to reach toxic threshold | **High-Yield:** This is a **high-yield NEET PG trap question**. Students often miss the allopurinol history and attribute leukopenia to azathioprine monotherapy. The key is recognizing the **drug–drug interaction**. ### Management 1. **Immediate:** Discontinue allopurinol 2. **Reduce azathioprine dose by 60–75%** if continuation is necessary 3. **Alternatively:** Switch to febuxostat (does not inhibit xanthine oxidase) for urate lowering 4. **Monitor:** CBC weekly until recovery 5. **Prognosis:** Leukopenia resolves within 1–2 weeks of allopurinol withdrawal **Clinical Pearl:** If a patient on azathioprine requires urate-lowering therapy, **febuxostat is the preferred choice** because it does not inhibit xanthine oxidase and avoids this interaction. **Mnemonic:** **AZA + ALLO = MARROW MELTDOWN** - **AZA** = azathioprine - **ALLO** = allopurinol - **MARROW MELTDOWN** = severe myelosuppression [cite:KD Tripathi 8e Ch 72]