Drug metabolism and bioanalysis letters最新文献

Sphingolipids are bioactive lipids that are essential for cellular functions like signaling, apoptosis, and proliferation. They are also important in the biology of cancer. The complex dynamics of sphingolipid metabolism and its consequences for the advancement of cancer are examined in this review. It highlights the regulatory functions of important enzymes such as ceramide kinase (CERK) and sphingosine kinases (SPHKs) in preserving the equilibrium between sphingosine-1-phosphate (S1P), a pro-survival chemical, and ceramides, which encourage cell death. Tumour growth, metastasis, and treatment resistance are all significantly affected by disturbances in this equilibrium. The review emphasizes the potential of sphingolipids as biomarkers for cancer prognosis and stratification, providing information on the course of the disease and the effectiveness of treatment. Their crucial functions in cellular signalling pathways that affect angiogenesis, immunological evasion, and drug resistance, all of which are linked to cancer, are also reviewed. Their role in the tumor microenvironment further highlights sphingolipids' significance as targets for novel therapeutic approaches. Improved clinical results and personalized cancer treatments are made possible by developments in sphingolipid biology and their potential as biomarkers. This thorough synthesis provides the groundwork for further studies that will use sphingolipid metabolism and signalling to create potent cancer treatments. In the fight against cancer, we can improve therapeutic efficacy and diagnostic accuracy by understanding these intricate relationships.

Introduction/objective: Glucuronidation and sulfonation enzymes conjugate compounds containing a hydroxyl group, while paraoxonase enzymes hydrolyze lactonecontaining compounds. 3-Hydroxy-6H,7H-chromeno [3,4-c]chromene-6,7-dione (3- hydroxy-V-coumarin) contains both a hydroxyl substituent and two lactone substructures and is strongly fluorescent. This study evaluates glucuronidation, sulfonation and hydrolysis of 3-hydroxy-V-coumarin reactions, which abolish its fluorescence.

Methods: Glucuronide, sulfate, and hydrolyzed product formation were confirmed using accurate LC-MS. Fluorescence-based multi-well plate assays were established to determine rates of glucuronidation, sulfonation and hydrolysis of 3-hydroxy-V-coumarin.

Results: A decrease in fluorescence correlated with the formation of conjugation or hydrolyzed metabolites of the reactions was observed. 3-Hydroxy-V-coumarin was glucuronidated by human UGT1A1, 1A3, 1A4, 1A7, 1A8, 1A9, 1A10, 2A1, 2B4 and 2B7 and by dog UGT1A1, 1A2 and 1A11, and sulfonated by human SULT1A1, 1A2 and 1E1. The results indicated that paraoxonase 2 hydrolyzed lactone of 3-hydroxy-V-coumarin. 3-Hydroxy-Vcoumarin interacted via a hydrogen bond with serine 221 and via hydrophobic interaction with phenyls 71 and 291 of paraoxonase 2. The hydrolysis rate of 3-hydroxy-V-coumarin was determined in ten rat tissues. In human liver cytosol, the hydrolysis was slower than in rat, mouse, dog, pig, rabbit, and sheep liver cytosol.

Conclusion: 3-hydroxy-V-coumarin is a new model substrate for studying glucuronidation, sulfonation and lactone hydrolysis reactions.

Aim: The relationship between CYP1A2 polymorphisms and the steady-state plasma levels of aripiprazole and its active metabolite, dehydroaripiprazole, were investigated in Japanese schizophrenic patients.

Background: It has been implied that cytochrome P450 (CYP) 1A2 may play a role in the metabo-lism of aripiprazole. Genetic variations in the CYP1A2 gene have been reported.

Objective: The authors investigated the relationship between 2 CYP1A2 polymorphisms, CYP1A2*C (-3860G>A) and CYP1A2*F (-163C>A), and the steady-state plasma levels/dose (C/D) ratios of aripiprazole and dehydroaripiprazole in Japanese schizophrenic patients.

Methods: All 89 subjects (46 males and 43 females) had been receiving 2 fixed daily doses of aripiprazole (24 mg; n=56 and 12 mg: n=33) for more than 2 weeks. No other drugs were used except flunitrazepam and biperiden. The plasma drug levels were determined by LC/MS/MS. These CYP1A2 polymorphisms were detected using polymerase chain reaction analysis.

Results: The mean C/D ratios of dehydroaripiprazole were significantly (P < 0.05) lower in patients with the A/A allele of CYP1A2*F than in those without the allele. No differences were found in the values of aripiprazole and the combination of aripiprazole and dehydroaripiprazole among the CYP1A2*F genotype. There were no differences in the values of aripiprazole, dehydroaripiprazole, or the combination of the 2 compounds among the CYP1A2*C genotype. The absence of the A allele of CYP1A2*F was correlated with the mean C/D ratios of dehydroaripiprazole (standardized partial correlation coefficient = 0.276, P < 0.01) by multiple regression analysis.

Conclusion: The findings of this study suggest that the CYP1A2*F polymorphism contributes at least partially to the variability in the steady-state plasma levels of dehydroaripiprazole.

Quantum computing is poised to advance drug metabolism studies and drug delivery system design by providing unparalleled precision in simulating molecular interactions and optimizing therapeutic strategies. In drug metabolism, quantum algorithms allow for the accurate modeling of complex enzyme dynamics, such as those involving cytochrome P450 enzymes, which play a pivotal role in drug biotransformation. These simulations offer insights into metabolic pathways, helping predict drug efficacy, potential toxicities, and interactions with other compounds. Additionally, quantum computing is transforming drug delivery system design by enhancing the development of nanocarriers, optimizing their targeting and release profiles, and minimizing off-target effects. Quantum models enable more efficient design of nanoparticles, liposomes, and other carriers by simulating their interactions with biological environments at the atomic level. Together, these innovations enable faster, more personalized drug development, reducing the need for extensive testing and offering a path toward safer, more effective treatments for complex diseases.

Background and objectives: The effects of antipsychotic agents, including dopamine D2 receptor blocking agents such as haloperidol, chlorpromazine, and sulpiride, and related compounds such as mirtazapine and sertraline, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with those of CYP2D6.1.

Methods: Dopamine was determined by high-performance liquid chromatography, and Michaelis constants (K_m), maximal velocity (k_cat) values for dopamine formation, and inhibition constants (Ki) of psychotropic agents were estimated.

Results: K_m values for all CYP2D6 variants decreased at lower concentrations, and kcat values for CYP2D6 variants except for CYP2D6.10 gradually increased with increasing haloperidol concentrations up to 5 or 10 μM. The k_cat/K_m values for all CYP2D6 variants increased at under 2.5 μM concentrations. Lower sertraline concentrations decreased K_m values for CYP2D6.10. Chlorpromazine at concentrations under 10 μM competitively inhibited the activities catalyzed by all variants; however, the activities for only CYP2D6.10 were increased by chlorpromazine at concentrations over 250 μM. Mirtazapine and sertraline similarly decreased dopamine formation among all variants except for CYP2D6.10. However, CYP2D6.10 inhibition by mirtazapine was weaker than that of the other variants, and sertraline decreased K_m values for CYP2D6.10.

Conclusion: Haloperidol and sertraline, but not sulpiride, decreased the Km and/or increased kcat values for CYP2D6. The present findings suggest that Dopamine D₂ receptor-blocking agents and related compounds may polymorphically affect dopamine formation catalyzed by CYP2D6 in the brain.

Background: Everolimus, an allosteric mechanistic target of rapamycin (mTOR) inhibitor, recently demonstrated the therapeutic value of mTOR inhibitors for Central Nervous System (CNS) indications driven by hyperactivation of mTOR. A newer, potent brain-penetrant analog of everolimus, referred to as (1) in this manuscript [(S)-3-methyl-4-(7-((R)-3-methylmorpholino)-2- (thiazol-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)morpholine,(1)] catalytically inhibits mTOR function in the brain and increases the lifespan of mice with neuronal mTOR hyperactivation.

Introduction: Early evaluation of the safety of 1 was conducted in cynomolgus monkeys in which oral doses were administered to three animals in a rising-dose fashion (from 2 to 30 mg/kg/day). 1 produced severe toxicity including the evidence of hepatic toxicity, along with non-dose proportional increases in drug exposure. Investigations of cross-species hepatic bioactivation of 1 were conducted to assess whether the formation of reactive drug metabolites was associated with the mechanism of liver toxicity.

Methods: 1 contained two morpholine rings known as structural alerts and can potentially form reactive intermediates through oxidative metabolism. Bioactivation of 1 was investigated in rat, human and monkey liver microsomes fortified with trapping agents such as methoxylamine or potassium cyanide.

Results: Our results suggest that bioactivation of the morpholine moieties to reactive intermediates may have been involved in the mechanism of liver toxicity observed with 1. Aldehyde intermediates trappable by methoxylamine were identified in rat and monkey liver microsomal studies. In addition, a total of four cyano conjugates arising from the formation of iminium ion intermediates were observed and identified. These findings may potentially explain the observed monkey toxicity. Interestingly, methoxylamine or cyano adducts of 1 were not observed in human liver microsomes.

Conclusion: The bioactivation of 1 appears to be species-specific. Circumstantial evidence for the toxicity derived from 1 point to the formation of iminium ion intermediates trappable by cyanide in monkey liver microsomes. The cyano conjugates were only observed in monkey liver microsomes, potentially pointing to cause at least the hepatotoxicity observed in monkeys. In contrast, methoxylamine conjugates were detected in both rat and monkey liver microsomes, with only a trace amount in human liver microsomes. Cyano conjugates were not observed in human liver microsomes, challenging the team on the drugability and progressivity of 1 through drug development. The mechanisms for drug-induced liver toxicity are multifactorial. These results are highly suggestive that the iminium ion may be an important component in the mechanism of liver toxicity 1 observed in the monkey.

Introduction: MKT-077 and its derivatives are rhodacyanine inhibitors that hold potential in the treatment of cancer, neurodegenerative diseases and malaria. These allosteric drugs act by inhibiting the ATPase action of heat shock proteins of 70 kDa (HSP70). MKT-077 accumulates in the mitochondria and displays differential activity against HSP70 homologs.

Methods: The four Plasmodium falciparum HSP70s (PfHSP70) are present in various subcellular locations to perform distinct functions. In the present study, we have used bioinformatics tools to understand the interaction of MKT-077 at the ADP and HEW (2-amino 4 bromopyridine) binding sites on PfHSP70s. Our molecular docking experiments predict that the mitochondrial and endoplasmic reticulum PfHSP70 homologs are likely to bind MKT-077 with higher affinities at their ADP binding sites.

Results: Binding analysis indicates that the nature of the identified interactions is primarily hydrophobic. We have also identified specific residues of PfHSP70s that are involved in interacting with the ligand.

Conclusion: Information obtained in this study may form the foundation for the design and development of MKT-077-based drugs against malaria.