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As a plausible explanation for the large interindividual variability in the pharmacokinetics of the neuroleptic agent haloperidol, the contributions of CYP3A isozymes (CYP3A4 and the polymorphic CYP3A5) predominantly involved in haloperidol bioactivation to the neurotoxic pyridinium species 4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HPP(+)) were assessed in human liver microsomes and heterologously expressed enzymes. Based on recent reports on drug-drug interactions between haloperidol and antidepressants including selective serotonin reuptake inhibitors, the inhibitory effects of antidepressants on the CYP3A4/5-mediated haloperidol bioactivation were also evaluated. HPP(+) formation followed Michaelis-Menten kinetics in microsomes, recombinant CYP3A4, and CYP3A5 with K(m) values of 24.4 +/- 8.9 microM, 18.3 +/- 4.9 microM, and 200.2 +/- 47.6 microM, respectively, and V(max) values of 157.6 +/- 13.2 pmol/min/mg of protein, 10.4 +/- 0.6 pmol/min/pmol P450, and 5.16 +/- 0.6 pmol/min/pmol P450, respectively. The similarity in K(m) values between human liver microsomal and recombinant CYP3A4 incubations suggests that polymorphic CYP3A5 may not be an important genetic contributor to the interindividual variability in CYP3A-mediated haloperidol clearance pathways. Besides HPP(+), a novel 4-fluorophenyl-ring-hydroxylated metabolite of haloperidol in microsomes/CYP3A enzymes was also detected. Its formation was consistent with previous reports on the detection of O-sulfate and -glucuronide conjugates of a fluorophenyl ring-hydroxylated metabolite of haloperidol in human urine. Finally, all antidepressants except buspirone inhibited the CYP3A4/5-catalyzed oxidation of haloperidol to HPP(+) in a concentration-dependent manner. Based on the estimated IC(50) values for inhibition of HPP(+) formation in microsomes, the antidepressants were ranked in the following order: fluoxetine, nefazodone, norfluoxetine, trazodone, and fluvoxamine. These inhibition results suggest that clinically observed drug-drug interactions between haloperidol and antidepressants may arise via the attenuation of CYP3A4/5-mediated 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol biotransformation pathways.
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http://dx.doi.org/10.1124/dmd.31.3.243 | DOI Listing |
Cureus
November 2024
Psychiatry, Mahatma Gandhi Memorial Medical College, Indore, IND.
Background The presence of psychiatric symptoms in pregnancy is a common occurrence that requires swift and effective management to avoid harm to self, caregivers, staff, and, above all, the reliant fetus. However, there is a dearth of knowledge, practical guidelines, and research in the context of managing agitated states of antenatal patients. To bridge this critical knowledge gap, this research endeavors to illuminate the practices surrounding the management of agitated pregnant women with respect to psychiatric emergencies in a tertiary care hospital.
View Article and Find Full Text PDFNeurotox Res
December 2024
Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Chronic use of typical antipsychotics can lead to varying motor effects depending on the timing of analysis. Acute treatment typically induces hypokinesia, resembling parkinsonism, while repeated use can result in tardive dyskinesia, a hyperkinetic syndrome marked by involuntary orofacial movements, such as vacuous chewing movements in mice. Tardive dyskinesia is particularly concerning due to its potential irreversibility and associated motor discomfort.
View Article and Find Full Text PDFMol Psychiatry
December 2024
Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
Tardive Dyskinesia (TD) can occur in people exposed to dopamine receptor antagonists (DRAs). Its clinical management remains challenging. We conducted a systematic review/random-effects network meta-analysis (NMA) searching PubMed/MEDLINE/PsycINFO/ClinicalTrials.
View Article and Find Full Text PDFACS Omega
December 2024
Laboratório de Química Biológica (LQB), Departamento de Química Orgânica, Instituto de Química, and INCT-Bio (CNPq), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-970, Brazil.
Schizophrenia (SCZ) is a multifactorial mental illness with limited knowledge concerning pathogenesis, contributing to the lack of effective therapies. More recently, the use of a nitric oxide donor named sodium nitroprusside (sNP) was suggested as a potential therapeutic drug for the treatment of SCZ. Despite the mixed results regarding the effectiveness of the sNP in reducing SCZ symptoms, successful trials on sNP in treatment-resistant SCZ were published.
View Article and Find Full Text PDFInt J Pharm
December 2024
Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, China. Electronic address:
Parkinson's disease confronts challenges in drug delivery due to the blood-brain barrier. Intranasal delivery bypasses the blood-brain barrier for improved drug bioavailability, yet narrow nasal space and brief retention time hinder clinical applicability. We conducted a Bromocriptine Mesylate-loaded PLGA nanoparticles co-modified with low molecular weight protamine (LMWP) and lactoferrin (Lf) (LMWP/Lf-BCM-NPs) for nose-to-brain delivery.
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