Cyclophosphamide requires hepatic activation to produce its active alkylating metabolite. It also causes a characteristic toxicity not shared by other alkylating agents when given without adequate hydration. What is this unique adverse effect and its causative metabolite?

• A Peripheral neuropathy caused by 4-hydroxycyclophosphamide accumulation
• B Pulmonary fibrosis from reactive oxygen species generated by phosphoramide mustard
• C Haemorrhagic cystitis caused by acrolein (a urinary toxic metabolite) — prevented by mesna ✓
• D Renal tubular toxicity from chloroacetaldehyde accumulating in collecting ducts

Explanation

Cyclophosphamide undergoes hepatic CYP2B6-mediated oxidation to 4-hydroxycyclophosphamide, which spontaneously forms aldophosphamide, and then either the cytotoxic phosphoramide mustard or the urotoxic byproduct acrolein. Acrolein is excreted in urine where it directly damages urothelial cells, causing haemorrhagic cystitis (presenting with dysuria, frequency and haematuria). Mesna (2-mercaptoethane sulfonate sodium) is given co-currently to provide free thiol groups in the bladder that irreversibly conjugate acrolein, detoxifying it. Busulfan and bleomycin cause pulmonary fibrosis; cisplatin causes nephrotoxicity.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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