Clinical Pharmacokinetics of Antipsychotics

Abstract

The antipsychotics are a chemically diverse group of heterocyclic compounds, which ameliorate many symptoms of schizophrenia. Most of the antipsychotics are very lipophilic and cross lipoidal membranes freely. When administered orally, they are well absorbed and undergo substantial pre-systemic elimination (bioavailability: 10-70%), are highly bound to plasma proteins (75-99%) and tissues, and are extensively distributed (VD: 100-1000 L). Primary route of elimination for most of antipsychotics is hepatic metabolism and biotransformation produces active metabolites. There is no linear relationship between the concentration of parent compound and different metabolites, and clinical relevance of pharmacologically active metabolites is not well understood. There are wide interindividual variabilities in pharmacokinetics, which result in large differences in steady-state plasma concentrations on the same dose regimen. The existence of optimal therapeutic ranges for most antipsychotics remains controversial. One of the major problems is the lack of well-designed studies that involve sufficient numbers of patients to clearly establish a therapeutic range for these drugs and is further complicated by the presence of a large number of pharmacologically active metabolites. However, the pronounced interindividual kinetic variabilities, combined with problems of noncompliance and drug interactions, and the delayed onset of clinical response in relation to initiation of treatment with antipsychotics are reasons why drug monitoring in conjunction with clinical status of the patient can be useful. Indications for antipsychotic drug monitoring include lack of response, non-compliance, toxicity, and drug interactions when other drugs are coadministered.

A systematic microdialysis study of dopamine transmission in the accumbens shell/core and prefrontal cortex after acute antipsychotics

“…During the initial phase of drug distribution, when most of the drug is still in the blood, highly lipophilic APs, like clozapine, quetiapine, haloperidol and chlorpromazine, rapidly equilibrate with the highly perfused brain compartment (Balant-Gorgia and Balant 1987;Byerly and DeVane 1996;Jann et al 1993;Javaid 1994;Johnson et al 2011;Nord and Farde 2011;Verghese et al 1991). In this phase, distribution to the less perfused peripheral compartments has not yet taken place.…”

“…No DA peak, but a progressive increase to a plateau, was observed in the core. The early shell DA peak would result from fast distribution of lipophilic AP to the highly perfused brain compartment (Balant-Gorgia and Balant 1987;Byerly and DeVane 1996;Jann et al 1993;Javaid 1994;Johnson et al 2011;Nord and Farde 2011;Verghese et al 1991). This interpretation is consistent with the observation that amisulpride and sulpiride, which slowly distribute to the brain, lack the initial peak (Mauri et al 1996;Rosenzweig et al 2002).…”

Phenylalanine kinetics are associated with tardive dyskinesia in men but not in women

“…However, given (a) the demonstrated altered Phe kinetics 2h-postchallenge in men with TD, (b) our prior demonstrated association between TD and PKU (a metabolic disorder in which the hepatic clearance of Phe is grossly deÞcient because of deÞciencies of the enzyme Phe hydroxylase) (Richardson et al 1986), and (c) the demonstrated role of hepatic clearance in the pharmacokinetics of neuroleptics (Javaid 1994;Lin et al 1994;Snoeck et al 1995;Byerly and De Vane 1996), we suggest that the quality of the hepatic clearance of Phe may also be related to TD in men.…”

“…Studies addressing the pharmacokinetics of neuroleptics have given little attention to sex or age di¤erences with most studies including only men or persons under 60 as subjects (Yonkers et al 1992;Ereshefsky and Lacombe 1993;Javaid 1994;Lin et al 1994;Darby et al 1995). Two clearance studies, however, have shown (a) clearance of the typical neuroleptic, thiothixene, was signiÞcantly greater in men, and signiÞcantly greater in those under 50 (Ereshefsky et al 1991), and (b) clearance of the atypical neuroleptic, risperidone, in a small number of subjects [young (mean age, 30) and elderly (mean age, 69)], was decreased in the elderly subjects (Snoeck et al 1995).…”

Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

“…Antipsychotic drugs such as pimozide, N-methyl-D-aspartate receptor (NMDAR) agonists/antagonists, γ-aminobutyric acid inhibitors and valproic acids are frequently prescribed for the management of various psychiatric disorders, including schizophrenia, acute/chronic psychosis, delusional disorders, depression and anxiety disorder (17)(18)(19)(20). These drugs have a long history of clinical use and tolerable safety in humans, and readily penetrate the BBB, which is particularly important for GBM (21). In the present review, an overview of various preclinical and clinical studies testing the efficacy of antipsychotics for the treatment of human malignancies, including GBM, is presented and the putative mechanisms for the anti-neoplastic actions of these antipsychotic drugs is reviewed.…”