Human cytochromes mediating in vitro metabolism of lurasidone
Wei, Zixuan.
2019
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The objective of this
study was to develop an in vitro metabolic profile for lurasidone to determine
pharmacokinetic parameters Vmax and Km, and to model potential drug-drug interactions.
Lurasidone was first approved for clinical use in the United States in 2010 as a
second-generation antipsychotic drug. Clinical studies have shown it has been a
successful agent when used to treat patients ... read morewith schizophrenia. It is also approved as
an adjunctive therapy with lithium or valproate for the treatment of bipolar I disorder
associated with major depressive episodes (MDEs). The in vitro metabolic profile of
lurasidone has been mentioned in the product label and in review articles, but the
scientific data has not been published (Greenblatt et al., 2018). We set up an
UPLC-MS/MS assay to analyze the biotransformation of lurasidone. Since cytochrome (CYP)
P450 3A enzymes are reported to be the principal isoform responsible for metabolizing
lurasidone, the main metabolite ID-14283 was measured to calculate Vmax and Km. This was
done by in vitro incubations with human liver microsomes (HLM) from adults. Based on the
inhibition screen study, lurasidone is mainly metabolized by CYP3A4 in vitro.
Ketoconazole and ritonavir were evaluated as potential inhibitors; the average IC50
value were 1.10 μM and 3.43 μM, respectively. These data suggest that
clinical interactions of lurasidone with CYP3 inhibitors are likely, though validation
is needed in clinical studies.
Thesis (M.S.)--Tufts University, 2019.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: David Greenblatt.
Committee: Jeffrey Blumberg.
Keyword: Pharmacology.read less - ID:
- x059cm964
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