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Metabolism of clozapine-N-oxid in disrupted cells of neuronal and blood cell origin
Numerous studies investigated the metabolism of clozapine using hepatic microsomal preparations (1). We investigated the in vitro capability of peripheral blood and neuronal cells for intracellular conversion of clozapine-N-oxid to clozapine.
Epstein-Barr virus transformed blood cells (B-lymphoblastoids) and neuronal cells of human origin (IMR32) were cultured, disrupted and after the addition NADPH (1mM) and clozapine-N-oxid (200µM) suspensions were incubated for different times at 37° C. Clozapine and its metabolites were determined by HPLC (reversed-phase, C18 column).
Only B-lymphoblastoids showed the ability for a generation clozapine-N-oxid from clozapine. If blood cells should take part in metabolism of drugs, their metabolic activity should have influence on the bioavailability of drugs. besides cellular metabolism, drug accumulating in the cytoplasm might be relevant for the generation of toxic metabolites with the consequence on cell viability.
(1) Fang, J et al. Naunyn Schmiedebergs Arch Pharmacol 385(5) (1998) 592–599