Determination of an antipsychotic agent (ICI 204,636) and its 7-hydroxy metabolite in human plasma by high-performance liquid chromatography and gas chromatography-mass spectrometry.
ICI 204,636 (I) is an orally active antipsychotic agent under development for the treatment of schizophrenia in humans. It is partially converted in animals to an active 7-hydroxy metabolite (II). Methods were developed for the simultaneous determination of both analytes in human plasma using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The analytes were extracted from plasma using phenyl solid-phase extraction columns. Quantification by isocratic HPLC was performed in the reversed-phase mode with detection at 250 nm. Extracts were derivatized to trimethylsilyl ethers for quantification by GC-MS using selected-ion monitoring. Both assays were evaluated for consistency of response, precision, accuracy and specificity. Limits of quantification for I and II by HPLC were 15 and 20 ng/ml, respectively; limits of quantification for I and II by GC-MS were 2 and 5 ng/ml, respectively. Both methods were applied to the analysis of clinical samples from oral dosing studies with I.
Pullen
R H
RH
Drug Disposition and Metabolism Department, ICI Americas Inc., Wilmington, DE 19897.
Palermo
K M
KM
Curtis
M A
MA
D014150:Antipsychotic Agents / Q000097:blood*; D002851:Chromatography, High Pressure Liquid; D003987:Dibenzothiazepines / Q000097:blood*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D000069348:Quetiapine Fumarate; D012015:Reference Standards
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; C074114:2-(2-(7-hydroxy-4-dibenzo(b,f)(1,4)thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol; D000069348:Quetiapine Fumarate