Crohn’s disease (CD) is an inflammatory bowel disease that requires medical treatment. The use of medications to treat CD is increasing worldwide, coinciding with the rising prevalence of the disease. However, research on the use of medications for CD has mostly focused on developed countries, and little research has been done on the status and trends in China. Thus, we conducted a nationwide study to ascertain the current status of treatment for CD patients in Chinese healthcare institutions. Data on inpatient prescriptions for CD were obtained from the Hospital Prescription Analysis Cooperative Project of China. We analyzed the trends in patient numbers and prescription expenditures in seven regions of China. Subgroup analyses were performed by age, gender and drug class. A total of 71,654,361 patients from 70 hospitals in seven major cities of China were included in the study. From 2018 to 2022, the proportion of patients with CD increased from 0.23 per 1000 patients to 0.40 per 1000 patients. Visits by CD patients increased from 3598 to 5389, and the relevant expenditure increased from 2.83 million Chinese Yuan in to 10.61 million Chinese Yuan. The 20–39 age group was the most predominant age of incidence. The prevalence in males was more than twice as high as in females. 5-aminosalicylic acid, enteral/parenteral nutrients, corticosteroids and biologicals were the main prescribed drugs. There was a clear upward trend in the use of biologicals, especially infliximab, which has become the most used prescription drug since 2020. This nationwide study indicates a significant increase in healthcare utilization and expenditures for CD in China from 2018 to 2022, concurrent with a paradigm shift in treatment from traditional therapies toward biologic agents, primarily infliximab. This shift, facilitated by national insurance coverage, underscores the need for pharmacoeconomic evaluations and optimized stewardship of advanced therapies. The findings establish a crucial baseline for informing future healthcare strategies for CD management in China.

The safety of statin use during pregnancy remains controversial. We aimed to evaluate the association between prenatal statin exposure and pregnancy outcomes in Asian women, including low birth weight, preterm birth, and congenital anomalies. We conducted a PRISMA-compliant systematic review and meta-analysis of studies in Asian populations evaluating prenatal statin exposure. PubMed, Embase, the Cochrane Library, Web of Science, and trial registries were searched through January 31, 2026. Eligible randomized and observational studies included Asian populations and reported low birth weight, preterm birth, or congenital anomalies. Adjusted risk ratios were pooled using random-effects inverse-variance models, and risk of bias was assessed with standard tools. Three nationwide observational cohort studies from Taiwan and South Korea were included in the quantitative synthesis, and one Indonesian randomized trial of pravastatin for preeclampsia prevention was reviewed qualitatively. Prenatal statin exposure was not associated with congenital anomalies (RR, 0.98; 95

Background:Herb-drug interactions (HDIs) have garnered significant attention in recent years. Objectives:To investigate the effects of acacetin on the pharmacokinetics of diazepam both in vivo and in vitro. Methods:Rat liver microsomes (RLMs) were incubated with diazepam and acacetin to determine the half-maximal inhibitory concentration (IC50) and inhibition constant (Ki) values of acacetin, as well as to evaluate its inhibitory effect on diazepam metabolism in vitro. For the in vivo experiment, twelve male Sprague-Dawley rats were randomly allocated into two groups (n = 6) and received either 50 mg/kg acacetin or vehicle for two weeks. Subsequently, diazepam (10 mg/kg) was administered to each rat. Blood samples (300 μL) were collected from the tail vein at 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, and 8 hours post-administration. The plasma concentrations of diazepam and its metabolites were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Results:The IC50 values for temazepam and nordiazepam in RLMs were 2.065 μM and 5.2 μM, respectively. The Ki values for temazepam and nordazepam demonstrated that acacetin inhibits diazepam metabolism in vitro. In vivo, pretreatment with acacetin increased the area under the curve (AUC) and maximum plasma concentration (Cmax) of diazepam, while significantly decreasing its apparent clearance (CLz/F, P < 0.05). The AUC values for temazepam and nordiazepam decreased, whereas their CLz/F values increased significantly (P < 0.05). PyMOL simulations indicated that acacetin and diazepam share the same cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (CYP2C19) binding pocket, suggesting that acacetin inhibits diazepam metabolism via competitive inhibition. Conclusions:Acacetin significantly altered the pharmacokinetics of diazepam both in vivo and in vitro, indicating a potential interaction between acacetin and diazepam. Therefore, the concomitant use of acacetin and diazepam in clinical practice should be approached with caution.

Globally, primary headache disorders, including migraine, tension type headache and cluster headache, are a leading cause of disability in children and adolescents. However, there has been a paucity of large-scale population-based studies to inform clinical decision making for paediatric patients. Consequently, we undertook a nationwide study to ascertain the current status of primary headache treatment in children and adolescents in China. The study was based on the Hospital Prescription Analysis Cooperative Project of China, in which prescription data were extracted from a database of adolescent and child patients with a primary headache disorder from 160 hospitals in nine major Chinese cities from 2019 to 2023. In this study, we first analysed the trends in children and adolescents with primary headache in China over the past 5 years, stratified by age and sex, and analysed the trends in prescribing patterns. We then explored the differences in prescribing patterns among different populations and patients with different types of diagnoses, with the aim of analysing the current status of treatment for children and adolescents with primary headache in Chinese healthcare institutions in a multi-dimensional approach. A total of 1735 outpatients were included. The majority of patients were 15–17 years of age (65.0

Plant alkaloid-based chemotherapeutic agents, including paclitaxel, vincristine, and irinotecan, play a crucial role in cancer treatment. However, their use is frequently associated with adverse drug events (ADEs), which can impact patient safety and treatment outcomes. Despite prior research, there is still a lack of comprehensive real-world data analysis to systematically investigate ADEs associated with these drugs. This study extracted ADE reports related to paclitaxel, vincristine, and irinotecan from the FDA Adverse Event Reporting System (FAERS) database up to Q4 2024. Data processing was conducted using MySQL and Statistical Analysis System software, and adverse events (AEs) were categorized based on the Medical Dictionary for Regulatory Activities (MedDRA) classification system. Disproportionality analysis was employed using 4 methodologies - reporting odds ratio (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and Multi-Item Gamma Poisson Shrinker (MGPS) - to detect statistically significant safety signals. Additionally, Weibull survival analysis was conducted to evaluate the time-to-onset distribution of ADEs, allowing for a deeper understanding of the temporal patterns of adverse reactions. A total of 31,007, 7389, and 12,049 ADE reports were retrieved for paclitaxel, vincristine, and irinotecan, respectively. Disproportionality analysis identified significant ADE signals across 27 system organ classes, with the most frequently reported AEs involving hematologic, gastrointestinal, neurological, and hepatic disorders. Novel ADE signals were detected for each drug: paclitaxel (10 new signals), vincristine (10 new signals), and irinotecan (8 new signals). Representative newly identified ADEs include dyspnea, flushing, and back pain for paclitaxel, febrile neutropenia, pancytopenia, and sepsis for vincristine, and neuropathy peripheral, malignant neoplasm progression, and pulmonary embolism for irinotecan. Time-to-onset analysis indicated that ADE occurrences predominantly peaked within the first 30 days of treatment, following an early failure pattern, suggesting that intensive monitoring during this period may be necessary. This study provides a comprehensive real-world safety evaluation of plant alkaloid-based chemotherapeutic agents, identifying both known and previously unreported ADEs. By leveraging large-scale FAERS data, multiple signal detection methodologies, and Weibull survival analysis, this research enhances the pharmacovigilance landscape, offering crucial insights for clinicians and regulatory authorities.

Salt-sensitive hypertension (SSBP) is a common form of hypertension which responds strongly to dietary sodium intake. It is also associated with a significantly higher risk of cardiovascular events and target organ damage. Traditional research has focused on how the vascular, renal and neuroendocrine systems regulate SSBP. However, this study explores the profound effects of a high-salt environment on the immune system and its central role in SSBP pathogenesis, revealing key innovative findings in this field. High salt intake activates multiple key signalling pathways (NF-κB, JAK/STAT, MAPK and the NLRP3 inflammasome) in immune cells, such as antigen-presenting cells, macrophages and Th17 cells, triggering significant oxidative stress and inflammatory cascades. Specific mechanisms include high salt inducing immune cells to perceive sodium ions through the ENaC channel and NCX1, activating the SGK1/FOXO1 axis and NFAT5 to drive Th17/Treg imbalance and the release of pro-inflammatory factors such as IL-6, IL-17A, TNF-α and IL-1β.), excessive ROS production and the resulting protein modifications create new antigens (e.g. IsoLG), and gut microbiota dysbiosis (e.g. reduced Lactobacillus and elevated TMAO) amplifies systemic inflammation by reducing short-chain fatty acids (SCFAs) and increasing endotoxin release, thereby activating TLR4/NF-κB and other pathways. This study emphasises the novel mechanisms by which these signalling pathways NF-κB as the core hub of inflammation; JAK2 in CD11c+ APC cells; and p38 MAPK in endothelial dysfunction and their interactions drive SSBP. These inflammatory processes impair vascular endothelial function, affect renal sodium excretion and promote renal fibrosis. They also form a vicious cycle with sympathetic nervous system activation, which collectively drives the onset and progression of SSBP. Understanding these immune-mediated inflammatory mechanisms provides an important theoretical basis for developing novel anti-inflammatory therapeutic strategies for SSBP, such as targeting specific signalling pathways or regulating intestinal microbiota.

ObjectiveTo date, no national-scale drug usage survey for adolescents with depression has been conducted in China, and the purpose of this study was to examine the national trends in prescriptions in Chinese adolescent depression patients from 2017 to 2021.MethodsPrescribing data were extracted from the Hospital Prescription Analysis Cooperative Project. The average number of patients per year, the cost of treatment, and the prescription patterns (monotherapy vs. combination therapy) were analyzed, and subgroup analyses were conducted depending on age, sex, and drug class.ResultsThe study included 674,099 patients from 136 hospitals located in nine major areas of China. Of all patients, the proportion of adolescents increased from 1.63% in 2017 to 6.75% in 2021. Visits by adolescent depression patients increased from 1,973 in 2017 to 9,751 in 2021, and the corresponding cost increased from 607,598 Chinese Yuan in 2017 to 2,228,884 Chinese Yuan in 2021. The incidence of adolescent depression among female individuals was far beyond that among male individuals. Combination therapy was more frequent than monotherapy, and the most commonly prescribed drugs were antidepressants, antipsychotics, antiepileptics, and antianxietics. Despite the use of sertraline decreasing from 47.90 to 43.39%, it was the most frequently used drug.ConclusionIn summary, the prescriptions and cost of treatment for adolescent depression patients both increased rapidly. The widespread use of those drugs with weak clinical evidence reflects the current state of China, which should arouse our attention. The study can provide references for clinical treatment decisions and a basis for more efficient allocation of healthcare resources by the government.

It has been reported that drug-drug interactions (DDIs) can affect the pharmacokinetics and pharmacodynamics of various oral drugs. To better understand the effects of azole antifungal drugs (ketoconazole, fluconazole, and itraconazole) on pyrotinib's pharmacokinetics, DDIs between pyrotinib and three azoles were studied with Sprague-Dawley (SD) rat liver microsomes in vitro. Additionally, in vivo pyrotinib metabolic experiment was also performed. Twenty-four male SD rats were randomly divided into four groups: the ketoconazole (40 mg/kg), fluconazole (40 mg/kg), itraconazole (40 mg/kg), and the control group. UPLC-MS/MS was used for the determination of Pyrotinib's plasma concentration in rats. In vitro experiments showed that IC50 values of ketoconazole, fluconazole and itraconazole were 0.06, 11.55, and 0.27 μM, respectively, indicating that these drugs might reduce the clearance rate of pyrotinib at different degrees. In rat studies, coadministration of pyrotinib with ketoconazole or fluconazole could dramatically increase the Cmax and AUC(0-t) values and decrease the clearance rate of pyrotinib, especially for ketoconazole. However, coadministration with itraconazole had no impact on the pharmacokinetic characters of pyrotinib. These data indicated that ketoconazole and fluconazole could significantly decrease the metabolism of pyrotinib both in vitro and in vivo. More attentions should be paid when pyrotinib is combined with azole antifungal drugs in clinic although further investigation is still required in future.

ObjectiveTo explore the clinical effects of siting bath with different concentrations sodium chloride solution combined with 0.1% metronidazole on perianal infection in patients with leukemia.MethodsA total of 202 patients in Hematology department of our hospital from June 2010 to May 2018，were randomly divided into experiment 1 group（41 patients），experiment 2 group（42 cases），experiment 3 groups（40 cases），control 1 group（39 cases）and control 2 group（40 cases）.Patients in experiment 1 group，experiment 2 group，experiment 3 group received siting bath with 0.9% sodium chloride solution，1.6% sodium chloride solution，and 3.0% sodium chloride solution respectively，combined with 0.1% metronidazole injection.Patients in control 1 group received siting bath with 0.1% metronidazole solution.Patients in control 2 group received siting bath with potassium permanganate solution.The therapeutic effects of perianal infection of 5 groups was compared.ResultsThe therapeutic effects of experiment 2 group and 3 group were better than that of control 1 group.The therapeutic effects of experiment 2 group and 3 group were better than that of control 2 group.The therapeutic effects of experiment 2 group and 3 group were better than that of experiment 1 group.The therapeutic effect of experiment 2 group was better than that of experiment 3 group（all P<0.05）.ConclusionThe therapeutic effects of siting bath with 1.6% sodium chloride solution and 3.0% sodium chloride solution combined with 0.1% metronidazole injection were better than that sitz bath with 0.1% metronidazole solution or potassium permanganate solution alone.What's more，the effect of 1.6% sodium chloride solution combined with 0.1% metronidazole injection was the best for perianal infection.

Taxifolin is a flavonoid. It has been used as a chemopreventive agent and supplement. It may have some beneficial effects to treat prostate cancer by suppressing androgen production in Leydig cells. The objective of the present study was to study the effects of taxifolin on androgen production of rat Leydig cells isolated from immature testis and some rat and human testosterone biosynthetic enzyme activities. Rat Leydig cells were incubated with 100μM taxifolin without (basal) or with 10ng/ml luteinizing hormone (LH), 10mM 8-bromoadenosine 3',5'-cyclic monophosphate (8BR), and steroid enzyme substrates (20μM): 22R-hydroxychloesterol, pregnenolone, progesterone, and androstenedione. The medium concentrations of 5α-androstane-3α, 17β-diol (DIOL) and testosterone were measured. Taxifolin significantly suppressed basal, LH-stimulated, 8BR-stimulated, pregnenolone-mediated, and progesterone-mediated androgen production by Leydig cells. Further study demonstrated that taxifolin inhibited rat 3β-hydroxysteroid dehydrogenase and 17α-hydroxylase/17, 20-lyase with IC50 values of 14.55±0.013 and 16.75±0.011μM, respectively. Taxifolin also inhibited these two enzyme activities in human testis with IC50 value of about 100μM. Taxifolin was a competitive inhibitor for these two enzymes when steroid substrates were used. In conclusion, taxifolin may have benefits for the treatment of prostate cancer.

Background: Only a subset of patients with excessive alcohol use develop alcoholic liver disease (ALD), though the exact mechanism is not completely understood. Once ingested, alcohol is metabolized by 2 key oxidative enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are 2 major ALDH isoforms, cytosolic and mitochondrial, encoded by the aldehyde ALDH1 and ALDH2 genes, respectively. The ALDH2 gene was hypothesized to alter genetic susceptibility to alcohol dependence and alcohol-induced liver diseases. The aim of this study is to determine the association between aldehyde dehydrogenase 2 (rs671) glu504lys polymorphism and ALD. Methods: ALDH2 genotyping was performed in 535 healthy controls and 281 patients with ALD. Results: The prevalence of the common form of the single nucleotide polymorphism rs671, 504glu (glu/glu) was significantly higher in patients with ALD (95.4%) compared to that of controls (73.7%, P o 0.0001). Among controls, 23.7% had the heterozygous (glu/lys) genotype compared to 4.6% in those with ALD (odds ratio [OR]1⁄4 0.16, 95% CI: 0.09-0.28). The allele frequency for 504lys allele in patients with ALD was 2.3%, compared to 14.5% in healthy controls (OR 1⁄4 0.13, 95% CI: 0.07-0.24). Conclusions: Patients with ALDH2 504lys variant were less associated with ALD compared to those with ALDH2 504glu using both genotypic and allelic analyses. Key Indexing Terms: Aldehyde dehydrogenase; Gene polymorphism; Alcoholic liver disease; Risk. [Am J Med Sci 2018;] (]):]]]–]]].] INTRODUCTION Excessive alcohol drinking is one of the most significant risk factors for health problems such as injuries, liver diseases and cancer. Drinking becomes excessive when it causes or elevates the risk for alcohol-related problems or complicates the management of other health problems. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), excessive drinking is defined as men who drink thern Society for Clinical Investigation. Published by Els www.ssciweb.org more than 4 standard drinks in a day (or more than 14 per week) and women who drink more than 3 drinks in a day (or more than 7 per week). Alcoholic liver disease (ALD) is a major adverse health event resulting from excessive drinking. Its pathogenesis is a multistep process consisting of a series of histopathologic changes. More than 90% of drinkers develop alcoholic steatosis which is reversible upon abstinence. However, if excessive alcohol use continues, the disease evier Inc. All rights reserved. 1

The invention discloses a beneficiation method of low-grade cuprite. The method comprises the steps of after grinding the low-grade cuprite, adding water for pulp conditioning, so as to obtain ore pulp; sequentially adding an ore pulp dispersing agent, a vulcanizing agent, a copper ore collecting agent and a foaming agent into the ore pulp for pulp conditioning, and carrying out flotation to obtain cooper rough concentrate I; sequentially adding the vulcanizing agent, the copper ore collecting agent and the foaming agent into the ore pulp for pulp conditioning, and carrying out flotation to obtain a copper middling product; and finally, sequentially adding an oxidizing agent, the vulcanizing agent, the copper ore collecting agent and the foaming agent into the pulp for pulp conditioning, and carrying out flotation to obtain cooper rough concentrate II. The method is applicable to flotation of cuprite type copper ore, various copper-containing minerals in the copper ore can be fully recycled, the method is particularly applicable to flotation of cuprite which is difficult to beneficiate, copper concentrate with the copper grade of 18%-21% can be obtained, the cooper recovery rate reaches 78%-85% and is remarkably increased, the production cost is reduced, and the economic benefits are improved.

We aimed at investigating the role of CYP2C9 in carvedilol O-desmethylation and identifying the effect of 35 CYP2C9 allelic variants we found in Chinese Han population on the in vitro metabolism of carvedilol. Recombinant CYP2C9 and CYP2D6 microsomes of the wild type were used to test and verify the enzymes involved in carvedilol O-desmethylation. Recombinant CYP2C9 microsomes of distinguished genotypes were used to characterize the corresponding enzyme activity toward carvedilol. 2–100 μM carvedilol was incubated for 30 min at 37 °C. The products were detected using high-performance liquid chromatography. CYP2C9 plays a certain role in carvedilol metabolism. Compared with wild-type CYP2C9*1, the intrinsic clearance (V max/K m) values of all variants toward carvedilol O-desmethylation were significantly altered. The variants exhibited significantly decreased values (from 30 to 99.8 %) due to increased K m and/or decreased V max values. We conclude that recombinant system could be used to investigate the enzymes involved in drug metabolism and these findings complement the database where CYP2C9 polymorphism interacts with biotransformation of exogenous substances like drugs and toxins.

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic enzyme that catalyzes the metabolism of a great number of therapeutic drugs. Up to now, >100 allelic variants of CYP2D6 have been reported. Recently, we identified 22 novel variants in the Chinese population in these variants. The purpose of this study was to examine the enzymatic activity of the variants toward the CYP2D6 substrate carvedilol in vitro. The CYP2D6 proteins, including CYP2D6.1 (wild type), CYP2D6.2, CYP2D6.10, and 22 other novel CYP2D6 variants, were expressed from insect microsomes and incubated with carvedilol ranging from 1.0 μM to 50 μM at 37°C for 30 minutes. After termination, the carvedilol metabolites were extracted and detected using ultra-performance liquid chromatography tandem mass-spectrometry. Among the 24 CYP2D6 variants, CYP2D6.92 and CYP2D6.96 were catalytically inactive and the remaining 22 variants exhibited significantly decreased intrinsic clearance values (ranging from ~25% to 95%) compared with CYP2D6.1. The present data in vitro suggest that the newly found variants significantly reduced catalytic activities compared with CYP2D6.1. Given that CYP2D6 protein activities could affect carvedilol plasma levels, these findings are greatly relevant to personalized medicine.

Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 40-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug-drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10 mu mol L-1 diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25 mu mol L-1 and Ki = 4.473 mu mol L-1 in human liver microsomes. Curcumin's mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 >= 100 mu mol L-1. The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.

Background: Mestranol is a widely used estrogen, which is converted into its active metabolite ethinyl estradiol by cytochrome P450 (CYP) 2C9. To comprehensively examine the enzymatic activity of reported CYP2C9 variants in Chinese individuals in response to mestranol, wild-type CYP2C9*1 and 35 allelic variants were highly expressed in Sf21 insect cell microsomes and used for the detection of their enzymatic values in vitro. These results showed that the majority of tested variants exhibited decreased clearance values compared to wild type, except for CYP2C9*40 and *36. Method: Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.25-8 μmol/l mestranol for 30 min at 37°C. Then, the production of the metabolite of mestranol, ethinyl estradiol, was analyzed using high-performance liquid chromatography. Results: Most CYP-catalyzed reactions were sufficiently described by classical Michaelis-Menten kinetic parameters (e.g., Km and Vmax), while 9 variants exhibited atypical or non-Michaelis-Menten kinetic values, which were largely due to the self-inhibitory effect in response to mestranol. Conclusion: This is the first report of these rare alleles for mestranol metabolism, which provides fundamental data for further clinical studies on CYP2C9 alleles for mestranol metabolism.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of endogenous and exogenous compounds. Human and rat liver microsomes were used to investigate the inhibitory effects of methoxychlor (MXC) and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on the activities of corresponding human and rat CYPs. Probe drugs were used to test the inhibitory effects of MXC and HPTE on human and rat CYPs. The results showed that MXC and HPTE inhibited both human CYP2C9 and rat liver CYP2C11 activity, with half-maximal inhibitory concentration (IC50) values of 15.47 ± 0.36 (MXC) and 8.87 ± 0.53 μmol/l (HPTE) for human CYP2C9, and of 22.45 ± 1.48 (MXC) and 24.63 ± 1.35 μmol/l (HPTE) for rat CYP2C11. MXC and HPTE had no effects on human CYP2C19 activity but inhibited rat CYP2C6 activity with IC50 values of 14.84 ± 0.04 (MXC) and 8.72 ± 0.25 μmol/l (HPTE). With regard to human CYP2D6 and rat CYP2D2 activity, only HPTE potently inhibited human CYP2D6 activity, with an IC50 value of 16.56 ± 0.69 μmol/l. Both chemicals had no effect on human CYP3A4 and rat CYP3A1 activity. In summary, MXC and HPTE are potent inhibitors of some human and rat CYPs.

The objective of this work was to investigate the effect of orally administered genistein on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Twenty-five healthy male SD (Sprague-Dawley) rats were randomly divided into five groups: A group (control group), B group (multiple dose of 100 mg/kg genistein for consecutive 15 days), C group (multiple dose of 50 mg/kg genistein for consecutive 15 days), D group (a single dose of 100 mg/kg genistein), and E group (a single dose of 50 mg/kg genistein). A single dose of imatinib is administered orally 30 min after administration of genistein (100 mg/kg or 50 mg/kg). The pharmacokinetic parameters of imatinib and N-desmethyl imatinib were calculated by DAS 3.0 software. The multiple dose of 100 mg/kg or 50 mg/kg genistein significantly (P<0.05) decreased theAUC0-tandCmaxof imatinib.AUC0-tand theCmaxof N-desmethyl imatinib were also increased, but without any significant difference. However, the single dose of 100 mg/kg or 50 mg/kg genistein has no effect on the pharmacokinetics of imatinib and N-desmethyl imatinib. Those results indicated that multiple dose of genistein (100 mg/kg or 50 mg/kg) induces the metabolism of imatinib, while single dose of genistein has no effect.

Oxcarbazepine (OXC), a second-generation antiepileptic drug, undergoes rapid reduction with formation of the active metabolite 10,11-dihydro-10-hydroxy-carbazepine (MHD) in vivo. In this study, a method for simultaneous determination of OXC and MHD in rat plasma using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS-MS) was developed and validated. Under given chromatographic conditions, OXC, MHD and internal standard diazepam were separated well and quantified by electrospray positive ionization mass spectrometry in the multiple reaction monitoring transitions mode. The method validation demonstrated good linearity over the range of 10-2,000 ng/mL for OXC and 5-1,000 ng/mL for MHD. The lower limit of quantification was 5 ng/mL for OXC and 2.5 ng/mL for MHD, respectively. The method was successfully applied to the evaluation of the pharmacokinetics of OXC and MHD in rats, with or without pretreatment by ketoconazole (KET) and voriconazole (VOR). Statistics indicated that KET and VOR significantly affected the disposition of OXC and MHD in vivo, whereas VOR predominantly interfered with the disposition of MHD. This method is suitable for pharmacokinetic study in small animals.

Background: In light of the growing number of cancer survivors, the incidence of cardiovascular complications in these patients had also increased, while the effect of apatinib on the pharmacokinetic of cardioprotective drug (carvedilol) in rats or human is still unknown. The present work was to study the impact of apatinib on the metabolism of carvedilol both in vitro and vivo. Methods: A specific and sensitive ultra-performance liquid-chromatography tandem mass spectrometry method was applied to determine the concentration of carvedilol and its metabolites (4′-hydroxyphenyl carvedilol [4′-HPC], 5′-hydroxyphenyl carvedilol [5′-HPC] and o-desmethyl carvedilol [o-DMC]). Results: The inhibition ratios in human liver microsomes were 10.28, 10.89 and 5.94% for 4′-HPC, 5′-HPC and o-DMC, respectively, while in rat liver microsomes, they were 3.22, 1.58 and 1.81%, respectively. The data in vitro of rat microsomes were consistent with the data in vivo that the inhibition of 4′-HPC and 5′-HPC formation was higher than the control group. Conclusion: Our study showed that apatinib could significantly inhibit the formation of carvedilol metabolites both in human and rat liver microsomes. It is recommended that the effect of apatinib on the metabolism of carvedilol should be noted and carvedilol plasma concentration should be monitored.