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.
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 (Km), maximal velocity (kcat) values for dopamine formation, and inhibition constants (Ki) of psychotropic agents were estimated.
Results: Km 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 kcat/Km values for all CYP2D6 variants increased at under 2.5 μM concentrations. Lower sertraline concentrations decreased Km 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 Km 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.
Introduction: This paper aimed to establish a method to help investigate the combination mechanism of traditional Chinese medicine from the metabolic perspective.
Background: Semen Strychni has been a frequently used herb in clinics for a long time. In traditional Chinese medical science, Semen Strychni always combinate with other herbs to modulate its nature of severe toxicity. However, the mechanism of the combination is still unclear. Previous research mostly focused on the components of the herbs. The metabolic processes of the main components of the Semen Strychni are also very important and have rarely been reported.
Objective: This study tended to develop a rapid and sensitive high-performance liquid chromatographic- tandem mass spectrometric (HPLC-MS/MS) method for the determination of two major metabolites of Semen Strychni in rat urine.
Methods: Chromatographic separation was carried out on a C18 column. Detection was performed by a selective reaction monitoring (SRM) mode via an electrospray ionization (ESI) source operating in the positive ionization mode. Analysis of analytes from rat plasma was carried out by protein precipitation using acetonitrile.
Results: The assay was validated in terms of specificity, precision, recovery, etc. The intra- and inter-day precision values were less than 13.1%. The recoveries at three levels were more than 69.1%. The method was then used to study the kinetic profiles of the metabolites of Semen Strychni in rat urine for the first time.
Conclusion: The results demonstrate that the established LC/MS method in this study is accurate and sensitive for the simultaneous determination of the two metabolites of Semen Strychni in rats' urine samples. This method could be a supplement to the plasma pharmacokinetics of Semen Strychni.
Bigels are a novel concept in contrast to previous gel formulations. To look like one gel, bigels are made by merging two gel phases at high shear rates. Colloidal gels can be the same (as in water-in-water bigels, which are phase-separated systems), the same but different, or a combination of a hydrogel and an oleogel. These colloidal gels are utilized to construct bigels (oleogel-in-hydrogel bigels or hydrogel-in-oleogel bigels). Bigels have appealing qualities like hydrophilic and hydrophobic properties, improved spreadability, improved drug penetration, higher stratum corneum hydration, and the capacity to control the drug release rate. Bigels' mechanical, structural, thermal, physical, rheological, and electrical properties are crucial to their practical and successful use in a variety of commercial applications. In this compilation, we have talked about the convenience and interest of bigels as a formulation for novel applications in the pharmaceutical, cosmetic, and food industries. The use of several notable bigels is also discussed in the paper. The Bigels are widely utilized in the food and pharmaceutical industries as well. The Bigels are now being researched as possible drug delivery matrices.
Background: Angiotensin II type 1 (AT 1) receptor antagonist (angiotensin receptor blocker [ARB]) called Olmesartan medoxomil (OLM) prevents angiotensin II from acting on the renin-angiotensin-aldosterone pathway, which is a crucial factor in the development of hypertension. OLM is reported to rapidly hydrolyze into its active metabolite, Olmesartan, in plasma after oral treatment.
Objective: The objective of the ongoing study was to develop an easy-to-use, precise, and reliable RP-HPLC method for the determination of Olmesartan in bulk as well as pharmaceutical dosage forms.
Methods: The stability indicating HPLC method for assay includes the use of Kromasil 100-5-C8 (100 mm × 4.6 mm) column, UV detector 265 nm, and mobile phase composition was a mixture of Acetonitrile: water (70:30) and flow rate of 1.0 mL/min. ICH guidelines were followed in the method's validation. To assess the method's specificity and stability in showing characteristics, stress degradation studies were carried out. The working standard solution of Olmesartan was exposed to 0.1 N HCl at room temperature, 0.1 N NaOH at room temperature, 30 percent hydrogen peroxide by volume, and UV radiation in order to conduct a degradation study.
Results: The retention periods of the drug were found to be 1.36 and 1.47 min for standard and sample solutions, respectively. The degradation behaviour of drug under different conditions was studied. The drug was found susceptible to acidic, alkaline and oxidative conditions while it was found stable in photolytic condition. The developed stability-indicating RP-HPLC method for assay was validated as per ICH Q2 guidelines and the validation parameters such as accuracy, precision and specificity were obtained within the accepted criteria.
Conclusion: It may be concluded that this method is stability-indicating and specific and can successfully be applied to analyze tablet dosage form containing Olmesartan.
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