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The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with β-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Clearance of Aβ is a promising therapeutic strategy for AD. We have previously demonstrated that peripheral organs play important roles in the clearance of brain-derived Aβ. In the present study, we recruited 46 patients with liver cirrhosis and 46 normal controls and found that plasma Aβ40 and Aβ42 levels were significantly higher in the cirrhosis patients than in the normal controls. Notably, cirrhosis patients with hepatitis B virus (HBV) infection had higher plasma Aβ40 and Aβ42 levels than HBV-negative cirrhosis patients. Besides, cirrhosis patients had significantly higher plasma levels of interleukin-1β (IL-1β) and IL-6. Plasma tumor necrosis factor α (TNF-α) and interferon-γ (IFN-γ) levels were not significantly different between the groups. Moreover, we found significant correlations of hepatic functions with plasma Aβ40 and Aβ42 levels. Plasma IL-6 levels were also significantly correlated with plasma Aβ40 levels. However, in the linear regression model, we found significant correlation of plasma Aβ40 levels with hepatic functions, but not with plasma IL-6 levels. Our results indicate that the hepatic dysfunctions might result in decreased peripheral Aβ clearance by the liver. Protecting hepatic functions might be helpful for the clearance of brain-derived Aβ in the blood.

The aim of this study was to identify pharmacogenomic biomarkers to predict tegafur-uracil (UFT)-induced liver dysfunction. A total of 68 patients, who were administered UFT, were evaluated using a two-step pharmacogenomics analysis. The first screening revealed the association between five SNPs and UFT-induced hepatic dysfunction. In the second step, (rs4149056) was found to be the only SNP associated with UFT treatment-related elevation of aspartate aminotransferase (odds ratio: C/C vs T/T = 7.8, C/T vs T/T = 5.7; p = 0.037) and alanine transaminase (odds ratio: C/C vs T/T = 12.2, C/T vs T/T = 4.1; p = 0.034) levels. The polymorphisms are possible predictors of UFT treatment-related hepatic dysfunction.

To investigate the risk factors for postoperative hepatic dysfunction (HD) in patients undergoing acute Stanford type A aortic dissection (ATAAD) surgery and to develop an individualized prediction model. We retrospectively analyzed cardiac surgery patients with ATAAD treated at our hospital from January 2020 to March 2024, dividing them into 7:3 training and validation cohorts and grouping them into HD and non-HD categories based on postoperative liver function. Least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression were used to identify independent predictive factors for postoperative HD, which formed the basis of a nomogram prediction model. We assessed model accuracy, calibration and clinical utility using C-statistics, calibration plots and decision curve analysis (DCA) curves. Internal validation with 1000 Bootstrap resamples was performed to reduce overfitting bias. LASSO and multivariate logistic regression identified key risk factors for HD in ATAAD patients, including chronic kidney disease, preoperative creatinine, international normalized ratio (INR), red blood cell (RBC) transfusion volume, peak intraoperative lactate, aortic cross-clamping time greater than 99 min, and reoperation. Based on these factors, a nomogram prediction model was successfully developed. The Hosmer–Leme show test yielded a p value of 0.952, indicating a good model fit. The area under the curve (AUC) values in the training and validation cohorts were 0.856 (95% CI 0.777–0.936) and 0.958 (95% CI 0.915–1) respectively, indicating good discriminatory power. The calibration curve shows that the bias corrected line is close to the ideal line. The DCA curve indicates that the use of the nomogram provides greater net clinical benefit. The AUC values before and after Bootstrap validation were 0.860 (95% CI 0.795–0.924) and 0.858 (95% CI 0.795–0.924), respectively, reflecting stable model performance and minimal risk of overfitting. The internally validated prognostic nomogram demonstrates excellent discriminative power, calibration, and clinical utility for predicting the risk of HD in patients who have undergone ATAAD surgery. This allows for an individualized evaluation and the optimization of clinical outcomes.

Glycyrrhizin (GZ) is widely used to treat high-dose methotrexate (MTX)-induced liver dysfunction. However, in a previous in vivo study, we showed that simultaneous administration of both drugs increased the plasma concentration of MTX and exacerbated hepatic injuries. In this study, we investigated the optimal dosing interval in rats to avoid the interaction between high-dose MTX and GZ and to demonstrate the inherent hepatoprotective effect of GZ. Male Wistar rats were treated with high-dose MTX (2,000 mg/kg) alone, with concomitant administration of 100 mg/kg GZ or GZ administered 3, 6, and 24 h before MTX administration. Plasma concentrations of MTX, alanine aminotransferase, aspartate aminotransferase, and total bilirubin were measured. The plasma concentration and half-life of methotrexate were significantly increased after concomitant administration of GZ, or when GZ was administered 3 h before MTX administration, compared with MTX alone, increasing hepatic enzyme levels. However, when GZ was administered 6 and 24 h before MTX administration, the levels were not significantly different from those of MTX alone and showed a tendency to decrease MTX-induced liver injury. These results suggest that the pharmacokinetic interaction between GZ and MTX could be avoided and the hepatoprotective effect of GZ could be achieved by an optimal dosing regimen, using the half-life of GZ as an indicator. When using high-dose MTX in combination with GZ, the administration intervals should be considered to avoid unwanted interactions and to achieve the GZ hepatoprotective effect.

Background The efficacy and toxicity of voriconazole, a broad-spectrum antifungal agent, are correlated with its trough concentration (C trough ). Patients hospitalised in the intensive care unit (ICU) frequently experience inadequate voriconazole exposure. We sought to identify factors associated with variability of voriconazole C trough in ICU patients. Methods We searched MEDLINE, Web of Science and Cochrane Library databases from inception through July 2025. Results Thirty-one studies describing nine factors of variability were included. Liver dysfunction, high body mass index, high SOFA score and high inflammation status were associated with voriconazole overexposure, whereas the oral route of administration, renal replacement therapy and low body mass index were associated with voriconazole underexposure. The effects of extracorporeal membrane oxygenation and hypoalbuminemia on voriconazole exposure were unclear. Conclusions A systematic dose adaptation is required for patients with liver dysfunction, and voriconazole dose calculation should not be based on total body weight, with an adjusted body weight a preferred alternative. Intravenous administration should be favoured in patients without severe renal dysfunction. Further research to define the benefit of an individualised dosing approach for voriconazole in ICU patients that combines pharmacokinetic modelling and machine learning, is warranted. Meanwhile, close therapeutic drug monitoring is needed for ICU patients, especially those with identified risk factors for under- or overexposure. Graphical abstract

Microplastics (MPs) are ubiquitous in aquatic and terrestrial ecosystem, increasingly becoming a serious concern of human health. Many studies have explored the biological effects of MPs on animal and plant life in recent years. However, information regarding the effects of MPs on aging and lifespan is completely lacking in vertebrate species to date. Here we first confirm the bioavailability of MPs by oral delivery in the annual fish N. guentheri . We then show for the first time that administration of MPs not only shortens the lifespan but also accelerates the development of age-related biomarkers in N. guentheri . We also demonstrate that administration of MPs induces oxidative stress, suppresses antioxidant enzymes, reduces digestive enzymes, and causes hepatic dysfunction. Therefore, we propose that administration of MPs reduces lifespan of N. guentheri via induction of both suppressed antioxidant system and digestive disturbance as well as hepatic damage. Our results also suggest that smaller MPs appear more toxic to digestion, metabolism and growth of animals.

Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt the dose of anticancer agents for patients with renal or hepatic dysfunction. A guideline for anticancer agents was developed based on a literature search. An algorithm was generated to enhance the efficiency of the dose adaptation process. Finally, the dosing guideline was converted into an easy-to-use ExcelTM tool. The concept was applied to a total of 105 adult patients at the Centre for Integrated Oncology, Bonn, Germany. In total, 392 recommendations for dose adaptation were made and 320 (81.6%) recommendations were responded to by the oncologists. 98.4% of the recommendations were accepted. The algorithm simplifies the decision and screening process for high-risk patients. Moreover, it provides the possibility to quickly decide which laboratory tests are required and whether a dose adjustment for a particular anticancer drug is needed. The ExcelTM tool provides a recommended individual dose for patients with renal or hepatic dysfunction. The effectiveness of this strategy to reduce toxicity should be investigated in further studies before being adopted for routine use.

The malaria parasite mitochondrial proteins are critical targets for antimalarial drugs, however, the emergence of drug resistance against the existing protein targets necessitates novel therapeutic approaches. In this study, we profiled mitochondrial sense and natural antisense transcripts (NATs) in 22 Plasmodium falciparum clinical isolates, classified into three disease groups - uncomplicated malaria (UNC, n  = 6), cerebral malaria (CM, n  = 4), and hepatic dysfunction (HD, n  = 12), using a custom, strand-aware 60 K microarray, and validated the transcriptome using pooled, strand-specific RNA-seq (uncomplicated pool and complicated pool). Differential gene expression in the CM and HD cohort was obtained by comparing with uncomplicated malaria (UNC) as the control cohort. The analysis revealed distinct disease-specific sense and NATs, encoded by the mitochondrial genome, along with those encoded in the nucleus and targeted to the parasite mitochondria. Although mitochondrial activity is known to be reduced in blood-stage malaria, upregulation of genes linked to tricarboxylic-acid-cycle and electron-transport in the CM cluster indicates disrupted mitochondrial bioenergetics in severe disease. Profiling of sense and antisense mitochondrial transcripts reveal a correlated expression of sense-antisense transcript pairs in both the disease manifestations, indicating a potential regulatory role of NATs in mitochondrial function. These data provide direct evidence of NATs originating from the parasite mitochondrial genome and nominate key NATs against core mitochondrial functions as potential non-conventional antimalarial targets.

The univentricular Fontan circulation is associated with long-term multiorgan complications, including protein-losing enteropathy (PLE). While hemodynamic and lymphatic contributors to PLE have been described, its systemic metabolic signature remains incompletely characterized. We aimed to identify PLE-associated alterations in circulating metabolites using targeted serum metabolomics. Targeted serum metabolomic profiling was performed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using the AbsoluteIDQ p180 kit. Forty-nine individuals were included: Fontan patients with PLE (FPLE, n  = 10), Fontan patients without PLE (F, n  = 30), and clinically stable biventricular controls (C, n  = 9). Data were analyzed using MetaboAnalyst v6.0, including multivariate modeling (PLS-DA), univariate statistics with false discovery rate correction, correlation analyses, and receiver operating characteristic (ROC) analyses. Compared with controls, Fontan patients without PLE showed reduced concentrations of cholesterol, triacylglycerols, and several phosphatidylcholine (PC) species, whereas Fontan patients with PLE demonstrated relative increases in these lipid classes. Among 90 quantified PCs, 11 showed a consistent gradient with the lowest concentrations in F and the highest in FPLE. FPLE was further characterized by marked hypoalbuminemia and hypogammaglobulinemia, accompanied by elevated renin, aldosterone, and copeptin levels, indicating pronounced renal–neurohormonal activation of the renin-angiotensin-aldosterone system (RAAS) and vasopressin. Bile acid derivatives, including taurodeoxycholic acid and glycodeoxycholic acid, tended to be lower in FPLE and showed group-specific associations with both renin and selected PC species. Exploratory ROC-based screening identified the immunoglobulin G (IgG)-to-aldosterone and the albumin-to-PC ae C40:3 ratios as the most informative biomarker combinations distinguishing FPLE from non-PLE Fontan patients. These findings are exploratory and hypothesis-generating and require validation in independent cohorts. Fontan patients with PLE show a distinct metabolic phenotype integrating protein loss, lipid alterations, bile acid perturbations, and activation of the renin–angiotensin–aldosterone system. These findings suggest that metabolic and renal–neurohormonal pathways extend beyond lymphatic dysfunction in PLE and identify candidate biomarker patterns for further investigation rather than established diagnostic tools. Further studies are required to clarify causality, mechanistic links, and clinical generalizability.