Topiramate as an inhibitor of carbonic anhydrase isoenzymes

Purpose: This study investigated the effectiveness of topiramate (TPM) as a n inhibitor of six isozymes of carbonic anhydrase (CA). Methods: The inhibition constants (K-i) 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 purifi ed isozymes, erythrocytes, subcellular fractions of kidney or brain, and sa liva, and was assayed at 37 degrees C or 25 degrees C by O-18 mass spectrom etry and/or by measuring the pH shift at 0 degrees C. Results: Topiramate K-i values for HCA I, HCA II, HCA IV, and HCA VI were s imilar to 100, 7, 10, and >100 mu M, respectively. TPM K-i values for RCA I , RCA II, RCA III, RCA IV, and RCA V were similar to 180, 0.1 to 1, >100, 0 .2 to 10 and 18 mu M, respectively. For RCA II and RCA IV, the K-i values w ere temperature dependent. TPM K-i values for MCA II and MCA IV ranged betw een 1 and 20 mu M. 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.