Pharmacokinetics and Pharmacodynamics of Clozapine

摘要: The introduction of clozapine has given clinicians a unique agent for treating patients with schizophrenia that is refractory to other neuroleptics. Despite its efficacy, the drug continues be prescribed trepidation due incidence agranulocytosis. This article reviews pharmacokinetic and pharmacological properties clinical implications monitoring plasma concentrations. Various assays have been developed include gas-liquid chromatography, radioimmunoassay high performance liquid chromatography. Only few studies examined pharmacokinetics in schizophrenia. These revealed wide interpatient variability parameters include: time reach peak concentrations 1.1 3.6h; elimination half-life 9.1 17.4h; clearance 8.7 53.3 L/h; volume distribution 1.6 7.3 L/kg. Clozapine metabolised via hepatic microsomal enzyme system into 2 principle metabolites: demethyl-clozapine N-oxide. Urine samples reported ratio clozapine:demethyl:N-oxide 1:1:2. N-oxide binding affinity 3H-haloperidol was 4 times lower than conversion back hypothesised. Although exact mechanism action not fully understood, does possess significant different dopamine receptors, recent evidence supporting D4 receptor subtype. transiently increases serum prolactin levels minimal changes homovanillic acid levels. Limited investigating relationship between response investigated range 100 800 micrograms/L. In treatment schizophrenia, minimum concentration 350 micrograms/L suggested as needed. occurrence agranulocytosis could genetic basis should rigorously monitored during treatment. tardive dyskinesia extrapyramidal side effects minimal. can seizure threshold dose- time-dependent manner. Careful patient selection are required when therapy used