HUREL to UlotarontUlotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with
5-hydroxytryptamine type 1A (5-HT1A) and is in phase three of clinical development for the treatment of schizophrenia [i]. Ulotaront has demonstrated broad efficacy in animal and rodent assays that are sensitive to anti-depressants. Pre-clinical studies suggest that agonism at TAAR1 and 5-HT1A receptors contribute to ultotaronts efficacy. In a recent study, Dr. Guangqing Xiao et al., characterize the in vitro absorption, distribution, metabolism, and excretion (ADME) properties, preclinical pharmacokinetics (PK), and evaluate the drug-drug interactions (DDI) potential of ulotaront and its major metabolite SEP-383103. [ii] The role of NADPH-dependent and NADPH-independent enzymes in ulotaront metabolism and biotransformation to
SEP-383013 was investigated.

The Caco-2 monolayer system was used to test the permeability of ulotaront and SEP-383103. For the course of the transport assay, the ulotaront monolayers were incubated on an orbital shaker. To determine the concentration of ulotaront and SEP-383103, samples were taken at various timepoints, and their concentrations were measured by LC-MS/MS. Additionally, ulotaront’s in vitro metabolism was examined utilizing the HUREL ® model to determine whether cytochrome P450 2D6 (CYP2D6) and non-CYP enzymes are involved. For numerous timepoints, ulotaront was incubated with HUREL hepatocytes both with and without 1-aminobenzotriazole or quinidine. The disappearance of ulotaront following incubation was examined by LC-MS/MS. Additionally, in vitro CYP inhibition and induction assessment of ulotaront and SEP-383103, as well as assessment of ulotaront and SEP-383103 plasma and brain PK, were performed. It was revealed that ulotaront is an inhibitor of the renal transporter OCT2, but not of the transporters MATE1 or MATE2K, and phenotyping studies using recombinant human CYPs and FMOs revealed that the in vitro metabolism of ulotaront is primarily managed by CYP2D6. Ulotaront also showed low to moderate hepatic clearance in mouse, rat, monkey, and human hepatocytes.

Overall, Xiao et al., emphasize the efficacy of ulotaront, exhibiting high solubility, permeability, and low binding to plasma proteins. Visikol provides cutting-edge drug discovery solutions such as 3D cell culture assays and tissue imaging high content screening, blood brain barrier permeability assay, and  AI solutions for histological analysis of tissue sections, and much more. To learn more about Visikol’s services, please contact us.

[i] Synan, C et al., Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse liability and attenuates cocaine cue-induced relapse in rats. Drug and Alcohol Dependence 231 (2022) 109261

[ii] Xiao et al., In Vitro ADME and Preclinical Pharmacokinetics of Ulotaront a TAAR1/5-HT1A Receptor Agonist for the Treatment of Schizophrenia. Pharmaceutical Research (2022) 39:837–850


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