The affinities of a diverse set of 500 drug-like molecules to cytochrome P450 isoforms 2C9 and 2D6 were measured using recombinant expressed enzyme. The dose-response curve of each compound was fitted with a series of equations representing typical or various types of atypical kinetics. Atypical kinetics was identified where the Akaike Information Criterion, plus other criteria, suggested the kinetics was more complex than expected for a Michaelis-Menten model. Approximately 20% of the compounds were excluded due to poor solubility, and approximately 15% were excluded due to fluorescence interference. Of the remaining compounds, roughly half were observed to bind with an affinity of 200 microM or lower for each of the two isoforms. Atypical kinetics was observed in 18% of the compounds that bind to cytochrome 2C9, but less than 2% for 2D6. The resulting collection of competitive inhibitors and inactive compounds were analyzed for trends in binding affinity. For CYP2D6, a clear relationship between polar surface area and charge was observed, with the most potent inhibitors having a formal positive charge and a low percent polar surface area. For CYP2C9, no clear trend between activity and physicochemical properties could be seen for the group as a whole; however, certain classes of compounds have altered frequencies of activity and atypical kinetics.
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http://dx.doi.org/10.1021/jm0700060 | DOI Listing |
Ther Adv Drug Saf
December 2024
Genetics and Biochemistry Laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai 200030, China.
Background: Aripiprazole and risperidone, widely used atypical antipsychotics, are commonly adjunctively prescribed in clinical practice. When aripiprazole was combined with risperidone, the genotype of drug-metabolizing enzymes and liver impairment may lead to complex pharmacokinetic changes. The Physiologically Based Pharmacokinetic (PBPK) model can predict the influence of these factors on plasma concentration and optimize dosage regimens.
View Article and Find Full Text PDFKorean J Physiol Pharmacol
December 2024
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Olanzapine, an atypical antipsychotic, is widely used in the treatment of schizophrenia and bipolar disorder due to its modulation of dopamine and serotonin receptor systems. While its primary action involves antagonism of dopamine D2 and serotonin 5-HT (5-hydroxytryptamine)A receptors, recent evidence suggests that olanzapine also inhibits 5-HT receptors, which are ligand-gated ion channels involved in synaptic transmission in central and peripheral nervous systems. The present study aimed to investigate the action of olanzapine on 5-HT receptor-mediated currents using whole-cell voltage-clamp recordings in NCB-20 neuroblastoma cells.
View Article and Find Full Text PDFKorean J Physiol Pharmacol
December 2024
Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
The 5-hydroxytryptamine type (5-HT) receptor, a ligand-gated ion channel, plays a critical role in synaptic transmission. It has been implicated in various neuropsychiatric disorders. This study aimed to elucidate the mechanism by which quetiapine, an atypical antipsychotic, could inhibit 5-HT receptor-mediated currents in NCB20 neuroblastoma cells.
View Article and Find Full Text PDFTremor Other Hyperkinet Mov (N Y)
December 2024
National Clinical Research Center for Geriatric Disorders, Changsha, Hunan 410078, China.
Background: Postural tremor is a common clinical situation. Timely and accurate diagnosis is essential for effective treatment. However, clinicians often encounter difficulties distinguishing between essential tremor and other etiologies due to overlapping symptoms and atypical features.
View Article and Find Full Text PDFBr J Radiol
December 2024
Department of Radiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province 510515, China.
Objectives: To investigate the capability of morphological and enhancement pattern analysis in contrast-enhanced mammography (CEM) to differentiate between benign and malignant papillary breast lesions.
Methods: This study involved 63 patients diagnosed with papillary breast lesions between January 2018 and December 2022. CEM was performed at two time intervals: between 2-3 min (T1, early phase) and 4-5 min (T2, later phase) after the injection of the contrast agent.
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