Therapeutic monitoring of topiramate: evaluation of the saturable distribution between erythrocytes and plasma of whole blood using an optimized high-pressure liquid chromatography method.

Abstract

Topiramate (TPM) reportedly binds in a saturable manner to erythrocytes but minimally to plasma proteins. Two studies were performed to evaluate this distribution phenomenon. In all studies, TPM was measured with a newly developed, optimized procedure that uses octyldecyl (C-18) solid phase sorbents disks/packed cartridges and a DB-1 methylsilicone capillary gas chromatography (GC) column. Between-run precision coefficients of variation (CVs) (n = 16) ranged from 3.6%-5.6% at concentrations from 3.0 to 15 microg/mL, with low limit of detection of 0.2 to 0.3 microg/mL. For the distribution studies, drug-free whole-blood specimens from five healthy adult volunteers were supplemented with TPM and used to test the influence of TPM concentration and HCT differences on the plasma/blood (P/B) distribution ratio of TPM. In study A, TPM concentration was varied (1-15 microg/mL) and HCT remained constant (40% +/- 5%). In study B, TPM (3 microg/mL) was added to blood specimens comprising a range of HCT values (20%-40%). Study A results were: mean TPM P/B ratios: 0%, 14.2% +/- 5%, 44.2% +/- 4%, 76% +/- 5.5% at 1, 3, 5, 15 microg/mL, respectively. Data between each group were statistically different (p < 0.001). Study B results were: mean TPM P/B ratio: 17.3% +/- 7.3%, 27.5% +/- 10.1%, 39.8% +/- 8% and 56.1% +/- 8.8% at HCT values of 40%, 32%, 26.5%, 20%, respectively. The TPM P/B ratio was significantly inversely correlated to HCT (r = -905, p < 0.001). TPM P/B partitioning was not temperature-dependent. Researchers concluded that the saturable binding of TPM to RBC is significant and is correlated to HCT. As a result, TPM in the plasma fraction of whole blood will increase when HCT decreases and as total TPM concentration in whole blood increases.