Xenobiotica最新文献

Benzophenone-3, commonly known as oxybenzone, is an organic compound widely used in sunscreens and personal care products for protection against UVA and UVB rays. Due to its environmental persistence and potential toxicity, this study evaluated the effects of BP-3 at an environmentally relevant concentration (1 µg/L) on the gills, kidney, and antioxidant system of zebrafish (Danio rerio).Adult male zebrafish were randomly distributed into three groups, each with three replicates (n = 10 per group): water control, solvent control, and 1 µg/L BP-3, using a static exposure system for 96 hours. After the experiment, histopathological analyses of the gills and kidneys were performed, along with biochemical assessments of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT).Exposure to BP-3 resulted in significant histopathological alterations in the gills, including vascular congestion, epithelial detachment, edoema, and lamellar aneurysm, indicating severe damage to respiratory function. In the kidneys, glomerular capillary dilation, tubular cell vacuolisation, and focal necrosis were observed, suggesting renal dysfunction. Biochemical analyses revealed impairment of the antioxidant defense system: in the gills, SOD activity decreased, while CAT remained unchanged, indicating oxidative stress accumulation. In the kidneys, SOD activity significantly increased, while CAT decreased, suggesting enzymatic imbalance and cumulative oxidative damage.These results demonstrate that BP-3, even at low concentrations, induces significant histopathological and biochemical alterations in the gills and kidneys of D. rerio, highlighting its potential to compromise organ function and antioxidant defences. These findings underscore the need for stricter regulation of BP-3 release into aquatic environments to mitigate its ecotoxicological impacts and protect aquatic biodiversity.

Dolutegravir (DTG) is a key drug used to treat human immunodeficiency virus type-1 (HIV-1) infections. Adverse events (AEs) of DTG treatment, including headache, anxiety, depression, insomnia, and abnormal dreams, are influenced by sex, body weight, age, and serum bilirubin levels. DTG is mainly metabolised by members of the uridine diphosphate glucuronosyltransferase 1A subfamilies (UGT1As), especially UGT1A1.Some studies suggest a relationship between UGT1A1 variants and AEs. The aim of this study was to identify UGT1A isoforms that exhibit DTG glucuronidation activity and determine the relationship between UGT1A variants and DTG glucuronidation in vitro.UGT1A1, UGT1A3, UGT1A9, and UGT1A10 exhibited DTG glucuronidation activity, of which UGT1A1 was the most active. Furthermore, variants of these isoforms showed decreased DTG glucuronidation activity. The different variants of UGT1As, such as UGT1A1.6, UGT1A1.7, UGT1A1.35, UGT1A1.63, UGT1A3.5, UGT1A9.2, UGT1A10M59I, and UGT1A10T202I, showed reduced glucuronidation activity towards DTG in comparison with the wild-type UGT1As.This study elucidates the relationship between UGT1A variants and the levels of glucuronidation associated with each variant.Checking for UGT1As may be helpful in predicting potential toxicities and adverse effects related to DTG treatment.

The study investigated the effectiveness of pain care intervention combined with traditional Chinese medicine (TCM) care in the perioperative care of patients with urinary stones.Pain and urinary function recovery before and after postoperative care intervention, and Pittsburgh sleep quality index (PSQI), self-rating anxiety scale (SAS), and self-rating depression scale (SDS) scores before and after care intervention in the two groups were compared. First anal discharge time, catheter retention time, first out of bed activity time, the total number of hospital days, and complications were observed in both groups after surgery, and the satisfaction scores of patients in both groups with the perioperative care were recorded.Compared with the control group, the observation group showed lower first anal discharge time, catheter retention time, first out of bed activity time, the total number of hospital days, and the incidence of complications after surgery, and the patients were more satisfied with the care.Pain care intervention combined with TCM care is beneficial in reducing postoperative pain in patients undergoing urinary stone surgery, speeding up the recovery of urinary function, improving sleep quality, anxiety, and depression, and reducing the incidence of complications.

IBP (2,6-diisobornyl-4-methylphenol) is a camphene derivative with unique pharmacological properties and low toxicity. It exhibits pronounced antioxidant and membrane-protective effects, making it a promising cardio- and neuroprotector.The aim of the study was investigating the pharmacokinetics of IBP in rats after intravenous (1 mg/kg) and oral administration at three doses (10, 25, 50 mg/kg). Specifically, we focused on assessing the bioavailability and dose proportionality following oral administration.Blood samples were collected via a jugular vein catheter, and plasma samples were analysed using a validated HPLC-MS/MS method. The calculation of pharmacokinetic parameters was performed by both non-compartmental and compartmental approaches. The proposed dosage form for intravenous administration was a multicomponent mixture containing N-methyl-2-pyrrolidone.Concentration of IBP in the body after intravenous administration decreased over time, exhibiting bi-exponential decay kinetics. IBP reached peak concentrations immediately and was rapidly distributed into the peripheral compartment after intravenous administration. The systemic exposure after oral administration was proportional to the dose. The calculated absolute oral bioavailability of IBP was no more than 20%.The value of the average half-life of IBP after intravenous administration exceeded similar values after oral administration by 1.5-1.6 times.

Sorafenib and lenvatinib are systemic treatments for hepatocellular carcinoma. They often exhibit high intersubject pharmacokinetic variability and can cause drug-induced liver injury, yet the underlying mechanisms are poorly understood. Inhibition of some ATP-binding cassette (ABC) transporters, such as bile salt export pump (BSEP; ABCB11) and multidrug resistance-associated protein 2 (MRP2; ABCC2), which are involved in bile acid disposition, may lead to cholestatic liver injury.In this study, we investigated the inhibitory effects of sorafenib and lenvatinib on selected ABC transporters in membrane vesicles and sandwich-culture human hepatocytes (SCHH) using fluorescent probe substrates.The BSEP-mediated tauro-nor-THCA-24-DBD uptake was inhibited by sorafenib, with half-maximal inhibitory concentrations (IC₅₀) of 30.1 μM. Transport of Lucifer yellow by BCRP was strongly inhibited by sorafenib (IC₅₀ = 2.9 μM). Only sorafenib affected MRP2 activity (IC₅₀ = 15.6 µM). Both drugs showed comparable inhibition potency on P-gp with IC₅₀ values of 12.4 μM for sorafenib and 13.9 μM for lenvatinib. Unlike lenvatinib, sorafenib decreased the biliary excretion of tauro-nor-THCA-24-DBD, a probe substrate of BSEP, in SCHH by over 40%.In conclusion, sorafenib exhibited a more pronounced inhibition of ABC transporters, including BCRP, BSEP and MRP2, than lenvatinib, which could contribute to cholestatic liver injury.

Pulegone, an active component of the Chinese herb Mentha haplocalyx Briq., is primarily found in Mentha arvensis oil. It exerts toxic effects on the liver, nervous system, and kidneys, and its excessive intake leads to various adverse reactions and potentially fatal outcomes. CYP2E1 is considered the major metabolic enzyme that produces toxic metabolites of pulegone, which in turn cause toxicity in hepatocytes.This study aimed to establish a method for treating pulegone-induced acute liver injury via in vivo inhibition of CYP2E1 in mice.Acute liver toxicity was observed in mice intraperitoneally injected with 200 mg/kg pulegone, manifested as elevated serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), disorganisation of the hepatic lobular structure, degeneration of hepatocytes, karyopyknosis, apoptosis, and upregulation of inflammatory factors. Hepatic CYP2E1 expression was inhibited by the delivery of siRNA in lipid nanoparticles in mice.However, experimental results showed that si-Cyp2e1 LNPs could not ameliorate acute liver injury induced by pulegone. Interestingly, bicyclol could attenuate that liver injury in mice, which may be related to the inhibition of hepatocyte apoptosis.

A four-compartment model is presented that simulates inorganic mercury [Hg(II)] pharmacokinetics in blood, tissue, and excreta over a 70-day period. Simulations are validated against data collected from five human subjects, and previously analyzed.In the model, two compartments simulate Hg(II) in blood: one for mobile-Hg(II) and the other for immobile-Hg(II). Two corresponding compartments simulate Hg(II) in tissue. Mobile-Hg(II) represents Hg(II) available for transport across cell membranes. Immobile-Hg(II) represents Hg(II) that is not easily transported.Following dosing, blood total-Hg(II) droped rapidly in all subjects. Blood mobile-Hg(II) also droped rapidly with a concomitant rise in blood immobile-Hg(II). For four subjects, immobile-Hg(II) became the dominant Hg(II) species in blood by day 4. For subject five, mobile-Hg(II) remained dominant in blood for the study duration.Tissue mobile-Hg(II) declined rapidly for four of the subjects, with a simultaneous rapid rise in tissue immobile-Hg(II). In subject 5, tissue mobile-Hg(II) declined linearly, and immobile-Hg(II) accumulated slowly in tissue. For all subjects, tissue mobile-Hg(II) is the primary source of fecal Hg(II). The major source for Hg(II) excreted into the urine is immobile-Hg(II) from tissue.

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C₀) of venetoclax and the fluconazole C₀ were obtained from plasma samples on day 7 after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C₀ values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC_0-24 and C₀ of venetoclax were not associated with fluconazole C₀; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C₀ and fluconazole C₀ (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C₀. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C₀ is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

Polymorphisms in genes related to drug-metabolising enzymes may affect tacrolimus exposure. This study aimed to assess the influence of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus pharmacokinetics and outcomes in allogeneic haematopoietic stem cell transplantation (HSCT).Forty-six adult patients receiving oral tacrolimus at an initial dose of 0.03 mg/kg/day for acute graft versus host disease (GVHD) prophylaxis after allogeneic HSCT were enrolled in this retrospective study. Genetic polymorphisms were detected in relation to concentration/dose (C/D) ratios of tacrolimus and the incidence of acute GVHD and acute kidney injury (AKI).The CYP3A5 *3/*3 genotype and co-administration of voriconazole were significantly associated with increased C/D ratios of tacrolimus (p < 0.05). NR1I2 8055CC presents a significantly higher tacrolimus C/D ratio compared with carriers of 8055CT and 8055TT genotypes in allogeneic HSCT recipients with the CYP3A5*1 allele (p = 0.033). Younger age and recipients with the CYP3A5*1 allele were significantly associated with higher incidence of II-IV acute GVHD post-transplantation.CYP3A5*3, NR1I2 8055C > T, and concomitant use of voriconazole are important determinants affecting tacrolimus pharmacokinetics. Moreover, CYP3A5*1 allele and younger age are independent risk factors for II-IV acute GVHD in HSCT recipients.