Is Dextromethorphan Renal Toxic?
Dextromethorphan itself is not directly nephrotoxic when used at therapeutic doses, but its elimination is significantly affected by renal function, and overdose can cause renal injury. 1, 2
Metabolism and Renal Elimination
Dextromethorphan (DM) is primarily metabolized by the liver through CYP2D6 to its active metabolite dextrorphan, rather than being eliminated unchanged by the kidneys. 3 However, renal function plays an important role in the overall disposition of the drug:
In patients with chronic renal failure (creatinine clearance 20-70 ml/min), sparteine clearance and renal clearance of dextromethorphan metabolites are significantly decreased. 1
The fractional urinary excretion of dextrorphan (the active metabolite) is reduced by approximately 50% in renal failure patients compared to those with normal kidney function (median 24.4% vs 47.5%, p=0.02). 1
The amount of dextromethorphan excreted in urine correlates directly with creatinine clearance, independent of CYP2D6 metabolic activity. 1
Direct Nephrotoxicity Evidence
At therapeutic doses, dextromethorphan does not cause direct kidney damage. However, there is evidence of renal toxicity with overdose:
In animal studies using overdose conditions (0.1-0.4 mL/kg body weight for 28 days), dextromethorphan caused significant alterations in kidney function parameters including elevated creatinine, urea, and uric acid levels (p < 0.05). 2
Histopathological examination of kidney tissue in overdosed animals showed architectural changes consistent with renal injury. 2
These toxic effects occurred at doses 5-10 times higher than recommended therapeutic doses (megadoses used for recreational intoxication). 4
Clinical Implications for Renal Impairment
Dextromethorphan can be used in patients with renal impairment, but requires careful consideration:
Approximately 5% of persons of European ethnicity are CYP2D6 poor metabolizers who cannot metabolize dextromethorphan normally, leading to rapid accumulation and potential toxicity. 4
In poor metabolizers, dextromethorphan has a half-life of 29.5 hours compared to much shorter elimination in extensive metabolizers. 3
When renal function is impaired AND the patient is a poor metabolizer, drug accumulation risk is substantially increased. 1, 3
Important Caveats
The 2019 American Geriatrics Society Beers Criteria added the combination dextromethorphan/quinidine to the "use with caution" list, though this was based on limited efficacy and fall risk rather than direct nephrotoxicity. 5
Combination products containing dextromethorphan with acetaminophen, NSAIDs, or other ingredients may pose additional nephrotoxic risks from those other components, not from dextromethorphan itself. 4
Bottom line: Dextromethorphan is not nephrotoxic at therapeutic doses and does not require dose adjustment based solely on renal function, but overdose can cause kidney injury, and metabolite accumulation occurs in renal impairment. 1, 2