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Receptor binding profiles were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # NO1MH32004 (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. *Hot ligand: 3ff-Spiperone. #Hot ligand: 3ff-8-OH-DPAT.

Receptor binding profiles were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # NO1MH32004 (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. *Hot ligand: 3ff-Spiperone. #Hot ligand: 3ff-8-OH-DPAT.

profile was observed compared with the classical antipsychotics.106 Unlike typical antipsychotics, clozapine is largely devoid of EPS. The lack of EPS with this compound was postulated to be caused by its preferential binding to mesolimbic rather than striatal DA receptors.107 Furthermore, clozapine was shown to exhibit potent affinity for 5-HT2A receptors.108 When administered at a dose of 100 mg twice a day (bid [L. bis in die]), an average steady state plasma concentration of 319 ng/mL resulted at an average of 2.5 hours after administration. Because food does not apparently affect absorption, clozapine may be given with or without food. The compound is 97% bound to plasma proteins; however, interactions with other drugs have not been fully investigated.23 Clozapine is extensively metabolized after absorption with 50% of an administered dose excreted in the urine and 30% in the feces. Clozapine is metabolized to two major metabolites by n-oxidation and n-demethylation. Clozapine n-oxide (CZN0) is thought to be formed by the action of CYP3A4 and flavin monooxygenase 3 (FM03), whereas n-desmethyl-clozapine (DMCZ) appears to result by the action of CYP3A4 and CYP1A2 (Fig. 13.8).109 Clozapine also binds with high affinity at M1 and M4 muscarinic receptors in the limbic area of the brain.104 Whether affinity for muscarinic receptors contributes to the atypical profile for clozapine has not been established.103

DMCZ shows partial agonism at D2 and D3 receptors and exhibits a distinctly different pharmacological profile compared with clozapine and other atypical antipsychotics. Unlike clozapine, which is a potent M1 muscarinic antagonist, DMCZ is a potent M1 agonist. Agonism at muscarinic receptors has been proposed to be useful for impaired cognition in schizophrenia. Burnstein et al.110 found that DMCZ acted as a partial agonist at DA D2 and D3 receptors. These investigators suggested that the low incidence of EPS associated with clozapine may be caused by the partial agonism of DMCZ at D2 and D3 receptors. Thus, DMCZ may be of interest as an atypical antipsychotic with an improved side effect profile compared with clozapine.

Although clozapine demonstrates a favorable pharmacological profile compared with typical antipsychotics, its use is restricted by a relatively high incidence of agranulocytosis. The exact mechanism for the cause of agranulocytosis has not been confirmed, but a highly reactive nitrenium ion that is formed by the action of hepatic enzymes appears to be involved.111 The mean elimination half-life of clozapine

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