PT  - JOURNAL ARTICLE
AU  - Thomas I.F.H. Cremers
AU  - Gunnar Flik
AU  - Corry Hofland
AU  - Robert E Stratford, Jr.
TI  - Microdialysis Evaluation of Clozapine and N-desmethylclozapine Pharmacokinetics in Rat Brain
AID  - 10.1124/dmd.112.045682
DP  - 2012 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.112.045682
4099  - http://dmd.aspetjournals.org/content/early/2012/06/26/dmd.112.045682.short
4100  - http://dmd.aspetjournals.org/content/early/2012/06/26/dmd.112.045682.full
AB  - A significant barrier to realization of the full potential of clozapine as a therapeutic agent in the treatment of schizophrenia is the substantial inter-patient variability that exists along the therapeutic continuum of no response - efficacious response - adverse response. Genetic polymorphisms that manifest as highly variable pharmacodynamic and pharmacokinetic measures are its expected causes. In order to support investigations that seek to understand these causes, the plasma and CNS pharmacokinetics of clozapine were determined in rats, the latter using microdialysis sampling. Results obtained with clozapine and N-desmethylclozapine, a pharmacologically active human metabolite that was administered to a separate group of animals, support a conclusion of net carrier mediated efflux of both compounds across the BBB. These results are supported by the replication of published findings regarding the passive transport and net efflux transport of two model compounds, escitalopram and risperidone, respectively. The results obtained with clozapine and N-desmethylclozapine are considered a first step in the development of preclinical PK-PD models that will support deeper mechanistic studies of clozapine in vivo pharmacology, as well as the development of translational models that augment pharmacogenetic investigations that seek to improve the safety and efficacy of clozapine therapeutic intervention in the treatment of schizophrenia.