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

Richard P. Shank, Dennis R. Doose, Anthony J. Streeter, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

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 - 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 K d values of 0.54 and 140 μM, and Bmax values of 22 and 124 μmol/L of erythrocyte volume, respectively. These Bmax 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 CO2 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 (t1/2) that TPM has in blood compared to the CL/F, Vss/F and t1/2, estimated from plasma data. The difference between TPM blood and plasma pharmacokinetics was more profound at low doses (≤100 mg/day).

Original languageEnglish
Pages (from-to)103-112
Number of pages10
JournalEpilepsy Research
Volume63
Issue number2-3
DOIs
StatePublished - Feb 2005

Keywords

  • Blood-to-plasma ratio
  • CA-I
  • CA-II
  • Carbonic anhydrase
  • K
  • K
  • Pharmacokinetics
  • Topiramate

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