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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Iloperidone is an atypical antipsychotic with a low propensity to produce extrapyramidal side effects (Albers et al. 2008). It is a dopamine-D2/5-HT2 antagonist (Szewczak et al. 1995). Iloperidone is extensively metabolized via O-dealkylation, N-dealkylation, reduction, and hydroxylation in humans (Figure 3.24) (Mutlib et al. 1995). Iloperidone is O-dealkylated to form 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone (M2). Oxidative N-dealkylation results in 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazol and a secondary metabolite, 3-[(4-ace-tyl-2-methoxy)phenoxy]propionic acid (Mutlib et al. 1995). Iloperidone is reduced to 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzene methanol (M3), which is the major circulating metabolite in humans and rats (Mutlib et al. 1995). Hydroxylation of iloperidone yields 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl]-3-methoxyphenyl]-2-hydroxyethanone (M4) (Mutlib et al. 1995). M4 is further oxidized to 4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-piperidin1-yl]propoxy]-3-methoxyphenol (M5). In human liver microsomes, the formation of M4 is mediated by CYP2D6, while M2 is formed by CYP3A (Mutlib and Klein 1998). M3 is postulated to be produced mainly by a cytosolic enzyme, but CYP3A, 1A2, and 2E1 are involved in its formation as well (Mutlib and Klein 1998).
An update on the efficacy and safety of iloperidone as a schizophrenia therapy
Published in Expert Opinion on Pharmacotherapy, 2020
Ajay Nair, Amanie Salem, Anna-Lee Asamoah, Ravipreet Gosal, George T Grossberg
Iloperidone is an oral antipsychotic medication approved by the FDA in 2009 to treat schizophrenia. It has properties similar to second generation antipsychotics [12], with a relatively low incidence of EPS [5,21] and a potential to reduce negative symptoms, though overall efficacy in symptom reduction lags behind many other SGA medications [21]. The lack of a long acting formulation makes it a difficult medication to be given in populations that do not have a track record of good medication adherence, but its low incidence of weight gain [13] and hepatic side effects [33], as well as its potential to improve some areas of cognitive functioning [13,15,17], make it an interesting medication to try in specific patient populations. Particular caution should be used in patients that have a predisposition to orthostatic hypotension or priapism, and additional studies will be required to comment further on overall maintenance of schizophrenic patients of various demographics as well as the viability of its use in specific patient populations, such as those who are breastfeeding [35].
Development, characterization, comparative pharmacokinetic and pharmacodynamic studies of iloperidone solid SMEDDS and liquisolid compact
Published in Drug Development and Industrial Pharmacy, 2020
Dinesh Suram, Arjun Narala, Kishan Veerabrahma
Iloperidone is an atypical antipsychotic drug used for the treatment of schizophrenia [26]. Iloperidone is a BCS class II drug with reported oral bioavailability of 36% from a marketed oral dosage form due to low solubility and significant first pass effect [27]. This drug is suitable for studies to improve oral bioavailability. Schizophrenia is a mental illness caused by elevated dopamine levels. Dopamine is a neurotransmitter, and belongs to catecholamine family. Dopamine is produced in substantia nigra and ventral tegmental regions of brain and alteration leads to schizophrenia [28]. However, in the pathophysiology of schizophrenia, other neurotransmitters like glutamate, GABA, acetylcholine and serotonin were also involved according to recent research reports [29,30]. The mechanism of action of iloperidone in the treatment of schizophrenia was mediated by combined dopamine and serotonin antagonisms [26,31]. Antipsychotic drugs were reported to reduce the hyperlocomotion induced by MK-801 [32].
A descriptive study of aripiprazole, brexpiprazole, and cariprazine exposures in children ages 0 to 5 years reported to United States poison centers
Published in Clinical Toxicology, 2023
Nicholas Husak, Thomas W. Laudone, James B. Leonard
The results of our study are consistent with others evaluating newer antipsychotic exposures in young children. Stassinos and Klein-Schwartz [9] performed a similar study evaluating second generation antipsychotics. Drowsiness and lethargy occurred in over 50% for either asenapine, iloperidone, or lurasidone. The duration of effect in their study was generally short and coded as 8 to 24 h for a large proportion of the cases. In a separate study, they reported on the same age group for aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone [6]. Drowsiness/lethargy occurred in up to 48% of cases in our study. Medical outcomes in our study were consistent with the two published by Stassinos and Klein-Schwartz [6,9].