Ibuprofen-Induced Renal Tubular Acidosis

To the Editor:

Patil et al.¹ recently reported in this journal a patient with mixed renal tubular acidosis (RTA) after ibuprofen abuse. They suggested that carbonic anhydrase (CA) II inhibition by ibuprofen overdose may have led to RTA in this patient.¹ More than 16 patients with ibuprofen-induced RTA have been reported1, 2; however, these reports did not discuss the possible mechanisms of CA II inhibition by ibuprofen overdose. Greene et al.³ reported that ibuprofen can inhibit human erythrocyte CA II at more than several times to dozens of times higher concentrations than the concentrations at which ibuprofen is typically used as an analgesic. Timotheatou et al.⁴ previously proposed that ibuprofen, a carboxylate, directly binds to zinc through the negatively charged oxygen atoms of the carboxylate moieties, leading to CA inhibition. A recent review of CA inhibition mechanisms by Supuran⁵ showed that carboxylate compounds inhibit CA through direct binding to the catalytic zinc and displacing the bound water/hydroxide ion, anchoring to the zinc-coordinated water molecular/hydroxide ion, or occlusion of the entrance to the active site cavity. Thus, ibuprofen overdose may cause RTA due to CA inhibition through one of these mechanisms.