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

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 -Kd and maximum binding rate -Bmax) 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 Kd values of 0.54 and 140 microM, and Bmax values of 22 and 124 micromol/L of erythrocyte volume, respectively. These Bmax values are similar to literature values for the molar concentration of human CA-II (14-25 micromol/L) and CA-I (115-125 micromol/L). TPM inhibition constant (Ki) values for the inhibition of purified human CA obtained using assays based on CO2 hydration or 4-nitrophenylacetate hydrolysis were 0.62 and 0.49 microM for CA-II, and 91 and 93 microM 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 (< or = 100 mg/day).