Plasma and whole blood pharmacokinetics of topiramate: the role of carbonic anhydrase

Abstract Topiramate (TPM) is a broad-spectrum antiepileptic drug with various mechanisms of action including an inhibitory effect on some isozymes of carbonic anhydrase (CA). Binding to CA-I and CA-II, which are highly concentrated in erythrocytes, may affect drug pharmacokinetics. Consequently, the objectives of this study were: (a) to comparatively assess TPM pharmacokinetics in healthy subjects, based on plasma and whole blood data, by simultaneously measuring TPM concentrations in plasma and whole blood following different therapeutic doses; (b) to rigorously establish the affinity of TPM for CA-I and CA-II in order to gain insight into how binding to these isozymes in erythrocytes influences TPM pharmacokinetics. TPM (100, 200 and 400 mg, single dose) was given in a randomized three-way crossover design to 27 healthy subjects and the drug concentrations in plasma and whole blood were simultaneously measured for 168 h after dosing. The pharmacokinetics of TPM in plasma was linear, but TPM clearance from whole blood increased with increasing dose. At low therapeutic concentrations, the blood-to-plasma ratio for TPM decreased from 8 to 2 as its concentration increased, indicating a substantial and saturable binding of TPM to erythrocytes. The kinetics (dissociation binding constant – K d and maximum binding rate – B max ) of the binding of TPM to erythrocytes was determined from the measured concentrations of TPM in whole blood and plasma. This analysis indicated the existence of two binding sites with K d values of 0.54 and 140 μM, and B max values of 22 and 124 μmol/L of erythrocyte volume, respectively. These B max values are similar to literature values for the molar concentration of human CA-II (14–25 μmol/L) and CA-I (115–125 μmol/L). TPM inhibition constant ( K i ) values for the inhibition of purified human CA obtained using assays based on CO 2 hydration or 4-nitrophenylacetate hydrolysis were 0.62 and 0.49 μM for CA-II, and 91 and 93 μM for CA-I. The results of these studies indicate that virtually all of the binding of TPM to erythrocytes is attributable to CA-I and CA-II. Because CA-I and CA-II are highly concentrated in erythrocytes, a large portion of TPM in whole blood is bound and serves as a depot. This contributes to the lower oral clearance (CL/ F ), apparent volume of distribution (Vss/ F ) and longer half-life ( t 1/2 ) that TPM has in blood compared to the CL/ F , Vss/ F and t 1/2 , estimated from plasma data. The difference between TPM blood and plasma pharmacokinetics was more profound at low doses (≤100 mg/day).