ANALYSIS AND PHARMACOKINETICS OF OLANZAPINE (LY170053) AND 2 METABOLITES IN RAT PLASMA USING REVERSED-PHASE HPLC WITH ELECTROCHEMICAL DETECTION

A sensitive HPLC assay for measurement of the antipsychotic drug, olan zapine. in plasma has been developed. The assay has a limit of quantit ation of 1 ng ml(-1) in plasma and utilizes solid-phase extraction and electrochemical detection. The method provides a linear response for olanzapine over a concentration range of 1-100 ng ml(-1) with coeffici ents of determination greater than 0.9912. The inter-assay precision w as 15.9% at the limit of detection and ranged from 7.33% to 8.47% over the range of 5-100 ng ml(-1). The intra-assay precision was in the ra nge 0.97%-26.0%. The inter-assay accuracy ranged from 98.9 to 118% and the intra-assay accuracy ranged from 92.5% to 125% of the theoretical value. In addition, the assay was extended to measure the plasma leve ls of two metabolites of olanzapine, namely the N-desmethyl- and the 2 -hydroxymethyl analogs. The utility of the assay was demonstrated foll owing the administration of a single oral dose of C-14-olanzapine to r ats where, at several time-points after dosing, the plasma was assayed for total radioactivity, levels of olanzapine, and the two metabolite s. Olanzapine and two of its metabolites accounted for less than 50% o f the total plasma radiocarbon; olanzapine accounting for approximatel y 39% at the C-max, N-desmethyl for 5% and 2-hydroxymethyl for 8% resp ectively. The plasma elimination half-times for olanzapine and the two metabolites were approximately the same, ranging from 3.3 to 4.4 h.