Atomoxetine (ATX) is a neurological drug widely used for the treatment of attention deficit-hyperactivity disorder. Liver injury has been documented in patients administered ATX. The mechanism of ATX’s toxic action is less clear. This study is aimed to characterize reactive metabolites of ATX in vitro and in vivo to assist our understanding of the mechanisms of ATX hepatotoxicity. A hydroxylated metabolite, along with an O-dealkylation metabolite, was found in ATX-supplemented rat liver microsome incubations. Additionally, two glutathione (GSH) conjugates and two N-acetylcysteine (NAC) conjugates were observed in rat liver microsome incubations containing ATX, NADPH, and GSH or NAC. The corresponding GSH conjugates and NAC conjugates were found in bile and urine of ATX-treated rats, respectively. Recombinant P450 enzyme incubation study demonstrated that CYP2D6 dominated the metabolic activation of ATX. The insights gained from this study may be of assistance to illuminate the mechanisms of ATX-induced hepatotoxicity.
Wang Runze,Ren Xiaoqing,Liu Bingjie,Feng Yuqi,Zou Jing,Cao Jiaqi,Guo Mintong
Purpose Based on formulation optimization and pharmacokinetic (PK) assessment, an atomoxetine biphasic dissolving microneedle (DMN) system was developed. The system exhibits satisfactory mechanical properties and demonstrates an absorption profile superior to that of the oral dosage form. Methods A mechanically robust and rapidly DMN system was fabricated using a composite of pullulan (PL) and Gantrez AN-119 (GAN-119), with a polystyrene (PS) backing integrated to prevent drug migration. Comprehensive analyses were conducted to characterize the morphology, mechanical strength, hygroscopicity, drug content, and in vitro dissolution rate of the MNs. Furthermore, the pharmacokinetic profile of the DMN formulation was evaluated in rats and compared with that of oral administration at an equivalent dose, to assess the DMN’s potential for clinical application. Results A casting solution with PL-to-GAN-119 ratio of 4:1 provided optimal mechanical strength to the DMN tips, achieving 100% insertion efficiency. The use of a water-insoluble PS backing effectively prevented drug migration into the backing layer and significantly enhanced transdermal drug delivery. In vivo pharmacokinetic studies showed that the DMN group exhibited a T max of 1.0 h, a C max of 222.4 ± 12.1 ng·mL − 1 , and an AUC 0→24 h of 875.6 ± 69.0 ng·h·mL − 1 . In comparison, oral administration resulted in a T max of 2.0 h, a C max of 146.7 ± 8.2 ng·mL − 1 , and an AUC 0→24 h of 547.0 ± 39.2 ng·h·mL − 1 . These results indicate that, relative to oral delivery, the biphasic DMNs reached C max earlier and demonstrated higher bioavailability, as reflected by the increased AUC. Conclusion The PL/GAN-119 DMN system represents a promising strategy for the efficient transdermal delivery of atomoxetine. It enables rapid and enhanced systemic absorption while offering a scalable platform for future clinical translation.
The bitterness of a drug is a major challenge for patient acceptability and compliance, especially for children. Due to the toxicity of medication, a human taste panel test has certain limitations. Atomoxetine hydrochloride (HCl), which is used for the treatment of attention deficit/hyperactivity disorder (ADHD), has an extremely bitter taste. The aim of this work is to quantitatively predict the bitterness of atomoxetine HCl by a biosensor system. Based on the mechanism of detection of the electronic tongue (E-tongue), the bitterness of atomoxetine HCl was evaluated, and it was found that its bitterness was similar to that of quinine HCl. The bitterness threshold of atomoxetine HCl was 8.61 µg/ml based on the Change of membrane Potential caused by Adsorption (CPA) value of the BT0 sensor. In this study, the taste-masking efficiency of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) was assessed by Euclidean distances on a principle component analysis (PCA) map with the SA402B Taste Sensing System, and the host–guest interactions were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy (SEM). Biosensor evaluation and characterization of the inclusion complex indicated that atomoxetine HCl could actively react with 2-hydroxypropyl-β-cyclodextrin.
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