Chemical formula: C₁₈H₁₈ClN₃O Molecular mass: 327.808 g/mol PubChem compound: 3964
The efficacy of loxapine is proposed to be mediated through high affinity antagonism of dopamine D2 receptors and serotonin 5-HT2A receptors. Loxapine binds with noradrenergic, histaminergic, and cholinergic receptors, and its interaction with these systems may influence the spectrum of its pharmacological effects.
Changes in the level of excitability of subcortical inhibitory areas have been observed in several animal species, associated with calming effects and suppression of aggressive behaviour.
Administration of loxapine resulted in rapid absorption of loxapine with a median time of maximum plasma concentration (Tmax) by 2 minutes. Loxapine exposure in the first 2 hours after administration (AUC0-2h, a measure of early exposure that is relevant to the onset of therapeutic effect) was 25.6 ng*h/mL for the 4.5 mg dose and 66.7 ng*h/mL for the 9.1 mg dose in healthy subjects.
The pharmacokinetic parameters of loxapine were determined in subjects on chronic, stable antipsychotic regimens following repeat administration of loxapine every 4 hours for a total of 3 doses (either 4.5 mg or 9.1 mg). Mean peak plasma concentrations were similar after the first and third dose of loxapine, indicating minimal accumulation during the 4-hour dosing interval.
Loxapine is removed rapidly from the plasma and distributed in tissues. Animal studies following oral administration suggest an initial preferential distribution in the lungs, brain, spleen, heart and kidney. Loxapine is 96.6% bound to human plasma proteins.
Loxapine is metabolised extensively in the liver, with multiple metabolites formed. The main metabolic pathways include hydroxylation to form 8-OH-loxapine and 7-OH-loxapine, N-oxidation to form loxapine N-oxide, and de-methylation to form amoxapine. For loxapine, the order of metabolites observed in humans (based on systemic exposure) was 8-OH-loxapine >> loxapine N oxide > 7-OH-loxapine > amoxapine, with plasma levels of 8-OH-loxapine similar to the parent compound. 8-OH-loxapine is not pharmacologically active at the D2 receptor while the minor metabolite, 7-OH-loxapine, has high binding affinity to D2 receptors.
Loxapine is a substrate for several CYP450 isozymes; in vitro studies demonstrated that 7-OHloxapine is formed mainly by CYPs 3A4 and 2D6, 8-OH-loxapine is formed mainly by CYP1A2, amoxapine is formed mainly by CYP3A4, 2C19, and 2C8, and loxapine N-oxide is formed by FMOs.
The potential for loxapine and its metabolites (amoxapine, 7-OH-loxapine, 8-OH-loxapine, and loxapine-N-oxide) to inhibit CYP450-mediated drug metabolism has been examined in vitro for CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. No significant inhibition was observed. In vitro studies indicate that loxapine and 8-OH-loxapine are not inducers of CYP1A2, 2B6 or 3A4 enzymes at clinically relevant concentrations. In addition, in vitro studies indicate that loxapine and 8-OH-loxapine are not inhibitors of UGT1A1, 1A3, 1A4, 2B7 and 2B15.
Loxapine excretion occurs mainly in the first 24 hours. Metabolites are excreted in the urine in the form of conjugates and in the faeces unconjugated. The terminal elimination half-life (T½) ranged from 6 to 8 hours.
The mean plasma loxapine concentrations following administration of loxapine were linear over the clinical dose range. AUC0-2h, AUCinf, and Cmax increased in a dose-dependent manner.
A population pharmacokinetic analysis that compared exposures in smokers versus non-smokers indicated that smoking, which induces CYP1A2, had a minimal effect on the exposure to loxapine. No dosage adjustment is recommended based on smoking status.
In female smokers exposure (AUCinf) to loxapine and its active metabolite 7-OH-loxapine is lower than in female non-smokers (84% vs 109% 7-OH-loxapine/Loxapine Ratio), which is probably due to an increase in loxapine clearance in smokers.
There were no important differences in the exposure or disposition of loxapine following administration of loxapine due to age, gender, race, weight, or body mass index (BMI).
Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, and genotoxicity, except for changes to reproductive tissues related to the extended pharmacology of loxapine. Similar changes, e.g., gynecomastia, are known in humans, but only after long-term administration of medicines causing hyperprolactinaemia.
Female rats did not mate due to persistent diestrus after oral treatment with loxapine. Embryo/fetal developmental and perinatal studies have shown indications of developmental delay (reduced weights, delayed ossification, hydronephrosis, hydrourether, and/or distended renal pelvis with reduced or absent papillae) as well as increased numbers of perinatal and neonatal deaths in offspring of rats treated from mid-pregnancy with oral doses below the maximum recommended human dose for loxapine on a mg/m² basis.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
