Topiramate as an Inhibitor of Carbonic Anhydrase Isoenzymes

Abstract

Summary: Purpose: This study investigated the effectiveness of topiramate (TPM) as an inhibitor of six isozymes of carbonic anhydrase (CA). Methods: The inhibition constants (Ki) of TPM and acetazolamide (AZM) for CA I, CA II, CA III, CA IV, CA V, and CA VI were determined for human (HCA), rat (RCA), or mouse (MCA). The activity of CA was studied by using purified isozymes, erythrocytes, subcellular fractions of kidney or brain, and saliva, and was assayed at 37°C or 25°C by 18O mass spectrometry and/or by measuring the pH shift at 0°C. Results: Topiramate Ki values for HCA I, HCA II, HCA IV, and HCA VI were ∼100, 7, 10, and >100 μM, respectively. TPM Ki values for RCA I, RCA II, RCA III, RCA IV, and RCA V were ∼180, 0·1 to 1, >100, 0·2 to 10 and 18 μM, respectively. For RCA II and RCA IV, the Ki values were temperature dependent. TPM Ki values for MCA II and MCA IV ranged between 1 and 20 μM. Conclusions: These results indicate that TPM is more potent as an inhibitor of CA II and CA IV than of CA I, CA III, and CA VI. In all three species, AZM was usually 10 to 100 times more potent than TPM as an inhibitor of CA isozymes.