Development and validation of ultra-performance liquid chromatography-tandem mass spectrometric methods for simultaneous and rapid determination of contezolid and its major metabolite M2 in plasma and urine samples and its application to a study in subjects with moderate liver impairment.

Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment.

Effect of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intravenous Rivipansel.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose. All subjects in studies 1005 (n = 28) and 1006 (n = 16) completed all study procedures. Rivipansel exposure (AUCinf ) was 47%, 124%, and 437% higher and total clearance 30%, 57%, and 82% lower in the mild, moderate, and severe renal impairment groups, respectively, than in the normal renal function group. Overall rivipansel exposure was 20% lower and total clearance 31% higher in the moderate hepatic impairment group than in the normal hepatic function group. Ten treatment-emergent adverse events occurred in studies 1005 and 1006; no event was considered treatment related. As expected, clearance of rivipansel decreased with increasing renal impairment. The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment.

Untargeted metabolomic profiling of urine from healthy dogs and dogs with chronic hepatic disease.

Chronic hepatic disease can present a diagnostic challenge with different etiologies being associated with similar clinical and laboratory findings. The histopathological assessment of a liver biopsy specimen is usually required in order to make a definitive diagnosis and the availability of non-invasive prognostic biomarkers is limited. The emerging science of metabolomics is used to detect changes in endogenous low molecular weight metabolites in biological samples and offers the possibility of identifying noninvasive markers of disease. The objective of this study was to investigate differences in the urine metabolome between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Stored urine samples from 10 healthy dogs, 10 dogs with chronic hepatitis, 6 dogs with hepatocellular carcinoma, and 5 dogs with a congenital portosystemic shunt were analyzed. The urine metabolome was analyzed by gas chromatography-quadrupole time of flight mass spectrometry and 220 known metabolites were identified. Principal component analysis and heat dendrogram plots of the metabolomics data showed clustering between groups. Random forest analysis showed differences in the abundance of various metabolites including putrescine, gluconic acid, sorbitol, and valine. Based on univariate statistics, 37 metabolites were significantly different between groups. In, conclusion, the urine metabolome varies between healthy dogs, dogs with chronic hepatitis, dogs with hepatocellular carcinoma, and dogs with a congenital portosystemic shunt. Further targeted assessment of these metabolites is needed to assess their diagnostic utility.

Effect of hepatic impairment on the pharmacokinetics of vilaprisan: An open-label, single-dose, parallel-group study.

AIMS: The study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with hepatic impairment. Additionally, the safety and tolerability of vilaprisan were investigated. METHODS: In this phase 1, open-label, nonrandomised, parallel-group, pharmacokinetic study, men and women with mild or moderate hepatic impairment (Child-Pugh grade A or B) and control participants with normal hepatic function matched by age, weight and sex received a single oral 2 mg dose of vilaprisan. Key pharmacokinetic parameters, relationships between parameters and safety outcomes were measured. RESULTS: Thirty-six participants completed the study: 9 with mild hepatic impairment, 9 with moderate hepatic impairment and 18 matched control participants with normal hepatic function. Vilaprisan reached maximum plasma concentrations after 1-2 hours. Unbound vilaprisan exposure was 1.44-fold higher for participants with mild hepatic impairment vs controls (90% confidence interval: 0.91-2.26), and 1.74-fold higher for participants with moderate impairment vs controls (90% confidence interval: 1.09-2.78). The maximum observed unbound peak concentrations were similar for participants with hepatic impairment and matched controls. Vilaprisan 2 mg was well tolerated and the incidence of treatment-emergent adverse events was similar across cohorts. CONCLUSION: Only mild increases of <1.75-fold in exposure were observed in participants with mild or moderate hepatic impairment compared with control participants. No safety concern was identified. These data, alongside the excellent safety profile observed in phase 1 and 2 studies, do not indicate that a dose adjustment would be required in patients with mild or moderate hepatic impairment.

Bile acids and glucocorticoid metabolism in health and disease.

Glucocorticoids are regulators of stress response essential for survival. Liver disease can alter this homeostatic mechanism in patients with liver cirrhosis - a finding that might mirror the controversially discussed condition of critical illness related corticosteroid insufficiency. Underlying mechanisms might be shared molecular pathways in both bile acid as well as glucocorticoid metabolism at the level of synthesis, catabolism or the hypothalamus and the pituitary gland. Molecular links include the farnesoid X receptor FXR or the G protein-coupled bile acid receptor TGR5 expressed in the liver and the adrenals. In this review we sum up knowledge on the regulation of adrenal gland function and steroidogenesis, focussing on bile acids and potential alterations under cholestatic conditions, depict molecular links between glucocorticoid and bile acid metabolism and discuss the difficulties of assessment of adrenal function in humans in general and more specifically in liver diseases.

The relationship between urinary genistein levels and serum alanine aminotransferase levels in adults in the USA: National Health and Nutrition Examination Survey 1999-2010.

BACKGROUND: Genistein, a phytoestrogen with similarities to female sex hormones, has been shown to protect against oxidative stress and fibrosis in nonalcoholic fatty liver injury in animal studies. However, few studies have examined genistein's effects on liver function in humans. PARTICIPANTS AND METHODS: We analyzed data from the National Health and Nutrition Examination Survey from 1999 to 2010. Individuals younger than 21 years, with viral hepatitis, or with serum alanine aminotransferase (ALT) at the extremes of distribution (5% on each extreme) were excluded. Urinary genistein was normalized by urinary creatinine levels. The relationship between normalized urinary genistein (nUG) and serum ALT was examined using linear regression models with and without adjustment for potential confounders, and the differential effect of sex was examined using an interaction term. RESULTS: Of the 9864 participants, 52% were female, 50% were White, 24% were elderly, 36% had hypertension, 12% had diabetes, and 8.1% were heavy alcohol drinkers. Serum ALT was significantly lower in the highest quartile compared with the lowest quartile of nUG (22.3 vs. 23.5 U/l; P<0.001). In adjusted models, individuals in the highest quartile had 0.75 U/l lower ALT levels than those in the lowest quartile (P=0.02). We found a significant difference in ALT levels between the lowest and highest quartiles of nUG in males, but not in females (difference in differences=1.77 U/l, interaction P=0.04). CONCLUSION: We found a statistically significant association between higher nUG and lower serum ALT in males, but not in females. The sex-specific role of genistein in mitigating liver disease merits further study.

Increased oxidative damage of RNA in liver injury caused by hepatitis B virus (HBV) infection.

To evaluate the urinary levels of 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in liver injury patients with hepatitis B virus (HBV) infection and to explore the relationship between urinary 8-oxo-dGsn or 8-oxo-Gsn and degree of liver damage. We enrolled 138 liver injury patients with HBV infection and 169 age- and sex-matched healthy controls in this study. A sensitive and accurate isotope-diluted liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) method was used to measure the urinary levels of 8-oxo-Gsn and 8-oxo-dGsn. Simultaneously, pathological analysis of liver biopsy tissues was carried out, and immunohistochemistry was carried out for 8-oxo-Guo, 8-oxo-dGuo and MTH1 protein in some liver injury tissues. We analysed the correlation between the degrees of inflammation and fibrosis and levels of 8-oxo-Gsn and 8-oxo-dGsn. We also analysed the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn with clinical data of HBeAg, HBsAg, and HBV genotype and detected the levels of plasma aspartate aminotransferase, alanine aminotransferase (AST), platelet, alkaline phosphatase, prothrombin time (PT) and HBV DNA, and calculated the aspartate amino transferase-to-platelet ratio index (APRI) score. Nonparametric correlations were used to evaluate the correlation between 8-oxo-Gsn, 8-oxo-dGsn or APRI and various laboratory biochemical indicators. Results showed that the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn in patients with liver injury were significantly higher than those of healthy controls (both p < .001). Urinary 8-oxo-Gsn was significantly associated with AST, APRI and PT (p = .013, p = .026 and p = .049). The receiver operating characteristic curves of 8-oxo-Gsn were 0.696 (0.632-0.759) and 0.731 (0.672-0.790) for inflammatory activity and fibrosis, respectively. Patients with higher levels of urinary 8-oxo-Gsn are more likely to have a high degree of fibrosis and urinary 8-oxo-Gsn may have a great potential in assessing liver fibrosis.

El análisis de orina como herramienta diagnóstica en casos de malaria grave / Urinalysis as a diagnostic tool in severe malaria

Resumen La malaria produce complicaciones y muerte especialmente en poblaciones con acceso limitado a la atención en salud. La malaria grave puede reconocerse tempranamente mediante la detección en la orina de hallazgos como la hematuria, la coluria y la proteinuria. Se hizo una revisión narrativa basada en estudios sobre malaria grave y el empleo del análisis de orina mediante la consulta de 91 publicaciones. Mediante el análisis de la orina, se pueden detectar alteraciones metabólicas y lesiones en distintos órganos. En estudios recientes en Colombia se ha confirmado su utilidad como apoyo en el diagnóstico de la disfunción renal, la disfunción hepática y la anemia asociada con hemólisis, las cuales son complicaciones frecuentes en la malaria. El examen constituye una herramienta de fácil aplicación en la consulta ambulatoria y en pacientes hospitalizados para reconocer tempranamente casos complicados, y permite la detección oportuna de diferentes lesiones en el paciente con malaria, contribuyendo así a la reducción de la morbilidad grave y la mortalidad.

Abstract Malaria accounts for a significant morbidity and mortality rate around the world, especially in communities with limited access to healthcare. Some clinical signs in urine, like haematuria, coluria and proteinuria, help for the early diagnosis of severe malaria cases. A narrative review was conducted by analyzing 91 publications on studies about severe malaria cases and the use of urinalysis. A urinalysis can detect metabolic disturbances and organ injury. Its diagnostic utility for frequent complications caused by malaria, such as hepatic injury, kidney dysfunction and hemolysis, has been confirmed by recent Colombian studies. This test is an easy-to-use tool in outpatient clinics and with hospitalized patients to promptly recognize complicated cases, allowing the timely identification of different lesions in patients with malaria, thus contributing to the reduction of severe morbidity and mortality.

Luseogliflozin, an SGLT2 Inhibitor, in Japanese Patients With Mild/Moderate Hepatic Impairment: A Pharmacokinetic Study.

This open-label, parallel-group study evaluated the effect of mild and moderate hepatic impairment on the pharmacokinetics of a single dose of luseogliflozin in Japanese subjects. Thirteen subjects with hepatic impairment (mild, n = 8; moderate, n = 5) and 6 healthy subjects received a single 5-mg dose of luseogliflozin. Serial blood sampling over 72 hours and 24-hour urine collection were done for pharmacokinetic analysis of luseogliflozin and its metabolites and to measure pharmacokinetic and pharmacodynamic parameters, respectively. Demographic characteristics were similar at baseline for both groups. Geometric mean ratios of maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to infinity (AUCinf [90%CI]) of unchanged luseogliflozin were 1.02 (0.790-1.32) and 0.774 (0.580-1.03), respectively, on comparing patients with hepatic impairment with healthy subjects, and 0.939 (0.752-1.17) and 1.00 (0.780-1.28), respectively, in subjects with mild and moderate hepatic impairment. Although mean plasma concentrations of metabolites were slightly higher in patients with hepatic impairment versus healthy subjects, their time-course plasma concentrations were very low compared with those of unchanged luseogliflozin. Single-dose luseogliflozin 5 mg was well tolerated by study participants, indicating luseogliflozin dose adjustment is not necessary in patients with mild and moderate hepatic impairment.

Characterization of aminoaciduria and hypoaminoacidemia in dogs with hepatocutaneous syndrome.

OBJECTIVE To characterize aminoaciduria and plasma amino acid concentrations in dogs with hepatocutaneous syndrome (HCS). ANIMALS 20 client-owned dogs of various breeds and ages. PROCEDURES HCS was definitively diagnosed on the basis of liver biopsy specimens (n = 12), gross and histologic appearance of skin lesions (4), and examination of skin and liver biopsy specimens (2) and presumptively diagnosed on the basis of cutaneous lesions with compatible clinicopathologic and hepatic ultrasonographic (honeycomb or Swiss cheese pattern) findings (2). Amino acid concentrations in heparinized plasma and urine (samples obtained within 8 hours of each other) were measured by use of ion exchange chromatography. Urine creatinine concentration was used to normalize urine amino acid concentrations. Plasma amino acid values were compared relative to mean reference values; urine-corrected amino acid values were compared relative to maximal reference values. RESULTS All dogs had generalized hypoaminoacidemia, with numerous amino acid concentrations < 50% of mean reference values. The most consistent and severe abnormalities involved glutamine, proline, cysteine, and hydroxyproline, and all dogs had marked lysinuria. Urine amino acids exceeding maximum reference values (value > 1.0) included lysine, 1-methylhistidine, and proline. CONCLUSIONS AND CLINICAL RELEVANCE Hypoaminoacidemia in dogs with HCS prominently involved amino acids associated with the urea cycle and synthesis of glutathione and collagen. Marked lysinuria and prolinuria implicated dysfunction of specific amino acid transporters and wasting of amino acids essential for collagen synthesis. These findings may provide a means for tailoring nutritional support and for facilitating HCS diagnosis.

Blood mercury concentrations are associated with decline in liver function in an elderly population: a panel study.

BACKGROUND: Mercury is a toxic heavy metal and is known to affect many diseases. However, few studies have examined the effects of mercury exposure on liver function in the general population. We examined the association between blood mercury concentrations and liver enzyme levels in the elderly. METHODS: We included 560 elderly participants (60 years or older) who were recruited from 2008 to 2010 and followed up to 2014. Subjects visited a community welfare center and underwent a medical examination and measurement of mercury levels up to five times. Analyses using generalized estimating equations model were performed after adjusting for age, sex, education, overweight, alcohol consumption, smoking, regular exercise, high-density lipoproteins cholesterol, and total calorie intake. Additionally, we estimated interaction effects of alcohol consumption with mercury and mediation effect of oxidative stress in the relationship between mercury levels and liver function. RESULTS: The geometric mean (95% confidence interval (CI)) of blood mercury concentrations was 2.81 µg/L (2.73, 2.89). Significant relationships were observed between blood mercury concentrations and the level of liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT), after adjusting for potential confounders (P < 0.05). The odds ratios of having abnormal ALT levels were statistically significant in the highest mercury quartile compared to those with the lowest quartile. Particularly, regular alcohol drinkers showed greater effect estimates of mercury on the liver function than non-drinkers groups. There was no mediation effect of oxidative stress in the relationship between blood mercury concentrations and liver function. CONCLUSIONS: Our results suggest that blood mercury levels are associated with elevated liver enzymes and interact with alcohol consumption for the association in the elderly.

Urine albumin-to-creatinine ratio is associated with the severity of liver disease, renal function and survival in patients with decompensated cirrhosis.

BACKGROUND AND AIMS: To investigate if urine albumin-to-creatinine ratio (UACR) is associated with the presence of glomerular filtration rate (GFR) <60 mL/min, severity of liver disease and survival in patients with stable decompensated cirrhosis. METHODS: We evaluated prospectively 220 patients (73 % male, age 52.8 ± 12 years). In each patient, assessment of GFR was based on 51chromium-EDTA. Random urine samples were obtained for measurement of UACR. RESULTS: Thirty-eight patients (17 %, group 1) had UACR ≥30 mg/g and 182 (83 %, group 2) had UACR <30 mg/g. Group 1, compared to group 2 patients, had significantly lower levels of "true" GFR (61 vs. 71 ml/min, p = 0.035). Patients with "true" GFR <60 mL/min (n = 93), compared to those with "true" GFR ≥60 mL/min (n = 127), had higher levels of UACR (16 vs. 11.3 mg/g, p = 0.023). In multivariate analysis, serum creatinine and UACR (ΟR 0.98, 95 % CI 0.95-0.99, p = 0.04) were independently associated with the presence of GFR <60 mL/min. Based on the area under the ROC curves, the best cut-off point for UACR was >16.51 mg/g giving a sensitivity 70 %, specificity 49 %, PPV 68 % and NPV 51 %. During the follow-up period [17 (6-52) months], the patients who died or underwent LT (n = 158), compared to those who remained alive (n = 62), had higher levels of UACR (41 vs. 13 mg/g, p = 0.025). Patients with UACR ≥30 mg/g had worse outcome, compared to those with UACR <30 mg/g (log rank p = 0.053). CONCLUSIONS: We showed for the first time that UACR ≥30 mg/g was associated with more severe liver disease, lower GFR and worse LT-free survival in patients with decompensated cirrhosis. However, further studies are needed to confirm these findings.

[Urinalysis as a diagnostic tool in severe malaria].

Malaria accounts for a significant morbidity and mortality rate around the world, especially in communities with limited access to healthcare. Some clinical signs in urine, like haematuria, coluria and proteinuria, help for the early diagnosis of severe malaria cases.A narrative review was conducted by analyzing 91 publications on studies about severe malaria cases and the use of urinalysis.A urinalysis can detect metabolic disturbances and organ injury. Its diagnostic utility for frequent complications caused by malaria, such as hepatic injury, kidney dysfunction and hemolysis, has been confirmed by recent Colombian studies.This test is an easy-to-use tool in outpatient clinics and with hospitalized patients to promptly recognize complicated cases, allowing the timely identification of different lesions in patients with malaria, thus contributing to the reduction of severe morbidity and mortality.

Association between Aflatoxin M1 and Liver Disease in HBV/HCV Infected Persons in Ghana.

Aflatoxins are produced by the fungi Aspergillus flavus and Aspergillus parasiticus and are common food contaminants in tropical developing countries. Extensive aflatoxin consumption has been shown to be highly associated with liver disease. A case-control study was conducted to determine the association between aflatoxin and liver disease in Kumasi, Ghana. A questionnaire was administered to examine socio-demographic characteristics and food storage and consumption practices, and urine samples were collected to measure levels of the aflatoxin metabolite (AFM1). Two hundred and seventy-six people participated in the study; 38 had liver disease (cases), 136 had neither hepatitis B/C nor liver disease (negative controls), and 102 were hepatitis B/C positive without liver cancer (positive controls). A much higher percent of participants in each group was male (76% of cases, 88% of negative controls and 65% of positive controls). Multivariate analysis showed that age was a significant predictor for being a case when cases were compared to negative controls. The odds of being a case was 70% less for participants aged 25-34 years (odds ratios (OR) 0.30; 95% confidence interval (CI) 0.10-0.88) compared to those ≥45 years. For cases; Akans were seven times more likely to have AFM1 levels below the median when compared to other ethnic groups (OR 7; CI 1.41-34.68). When cases were compared to positive controls, they were 2.29 times more likely to report awareness of aflatoxin contamination of groundnuts (95% CI 1.06-4.91). Cases were also two times more likely to report awareness of aflatoxin contamination of maize than all controls combined (95% CI 1.02-4.11). However, most cases reported that aflatoxin contamination does not cause sickness in humans. This shows that there is awareness of aflatoxin contamination without proper understanding of the serious potential adverse health impacts among these study participants. These findings indicate that educational interventions that stress the harmful health effects of aflatoxin in food, with an emphasis on the higher risk for males, are urgently needed. The reasons for lower aflatoxin levels among Akans need to be determined, and the findings used to design interventions that benefit other ethnic groups in the society.

People with diabetes, respiratory, liver or mental disorders, higher urinary antimony, bisphenol A, or pesticides had higher food insecurity: USA NHANES, 2005-2006.

This study was aimed to examine the prevalence of food insecurity and what social, health, and environmental characteristics could constitute such situation in a national and population-based setting. Data was retrieved from the National Health and Nutrition Examination Survey, 2005-2006. Information on demographics, lifestyle factors, self-reported ever medical conditions in the past and self-reported food security conditions in the last 12 months calculated on the household level was obtained by household interview. Bloods and urines (subsample) were collected at the interview as well. Only adults aged 20 years and above (n = 4979) were included for statistical analysis in the present study. Chi-square test, t test, and survey-weighted logistic regression modeling were performed. Three thousand eight hundred thirty-four (77.9%) people were with full food security, 466 (9.5%) people were with marginal food security and 624 (12.7%) people were with low or very low food security. Being younger, having higher ratios of family income to poverty thresholds (due to low level of education or lack of financial support), having prior asthma, arthritis, chronic bronchitis, depression, diabetes, eczema, emphysema or liver problems, having higher levels of serum cotinine, urinary antimony, bisphenol A, pesticides, or having lower levels of urinary Benzophenone-3 were associated with food insecurity. In addition to socioeconomic and smoking conditions, evidence on people with several prior health conditions and being exposed to environmental chemicals and food insecurity is further provided. Future social, health and environmental policy, and programs protecting people from food insecurity by considering both health and environmental factors mentioned above would be suggested.

A Laboratory Diagnostic Approach to Hepatobiliary Disease in Small Animals.

Routine biochemical tests generally include serum enzymes, proteins, and other markers useful for identifying hepatobiliary disease in dogs and cats. Obtaining results outside the reference intervals can occur with direct hepatocellular injury, enzyme induction by hepatocytes or biliary epithelium, or decreased hepatic function. However, detection of biochemical abnormalities does not necessarily indicate clinically significant disease. For a comprehensive approach to detection and treatment of hepatobiliary disease, the laboratory results must be correlated with the history and physical examination findings, diagnostic imaging results, and other assays.

Urinary bile acids as biomarkers for liver diseases I. Stability of the baseline profile in healthy subjects.

The role of bile acids (BAs) as biomarkers for liver injury has been proposed for decades. However, the large inter- and intra-individual variability of the BA profile has prevented its clinical application. To this end, we investigated the effect of covariates such as food, gender, age, BMI, and moderate alcohol consumption on the BA profile in healthy human subjects. The BA profile was characterized by the calculation of indices that describe the composition, sulfation, and amidation of total and individual BAs. Both inter- and intra-individual variabilities of BA indices were low in serum and even lower in urine compared with those of absolute concentrations of BAs. Serum BA concentrations increased with consumption of food, whereas urinary BA concentrations were mildly affected by food. Gender differences in the urinary and serum BA profile were minimal. The serum and urinary BA profiles were also not affected by age. BMI showed minimal effect on the urine and serum BA profile. Moderate alcohol consumption did not have a significant effect on the BA profile in both urine and serum. When the effect of the type of alcohol was studied, the results indicate that moderate drinking of beer does not affect BA concentrations and has minimal effect on BA indices, whereas moderate wine consumption slightly increases BA concentrations without affecting the BA indices. In summary, urinary BA indices showed lower variability and higher stability than absolute BA concentrations in serum and showed minimal changes to covariate effects suggesting their utility as biomarkers in clinic.

Urinary bile acids as biomarkers for liver diseases II. Signature profiles in patients.

Hepatobiliary diseases result in the accumulation of bile acids (BAs) in the liver, systemic blood, and other tissues leading to an unfavorable prognosis. The BA profile was characterized by the calculation of indices that describe the composition, sulfation, and amidation of total and individual BAs. Comparison of the urinary BA profiles between healthy subjects and patients with hepatobiliary diseases demonstrated significantly higher absolute concentrations of individual and total BAs in patients. The percentage sulfation of some individual BAs were different between the two groups. The percentage amidation of overall and most individual BAs was higher in patients than controls. The percentage of primary BAs (CDCA and CA) was higher in patients, whereas the percentage of secondary BAs (DCA and LCA) was lower in patients. BA indices belonging to percentage amidation and percentage composition were better associated with the severity of the liver disease as determined by the model for end-stage liver disease (MELD) score and disease compensation status compared with the absolute concentrations of individual and total BAs. In addition, BA indices corresponding to percentage amidation and percentage composition of certain BAs demonstrated the highest area under the receiver operating characteristic (ROC) curve suggesting their utility as diagnostic biomarkers in clinic. Furthermore, significant increase in the risk of having liver diseases was associated with changes in BA indices.

Validation and impact of a new technique for assessment of glomerular filtration rate in patients with liver disease.

OBJECTIVES: Previously we have proposed a technique for the measurement of plasma clearance in patients with ascites. The impact of using the technique was assessed and the results compared with those from a reference technique in 111 patients having glomerular filtration rate measurements as part of their workup for liver transplantation. METHODS: Results of calculations using the new technique were compared with plasma clearance measurements obtained using a conventional slope-intercept technique and with clearance measurements based on urine collection. Discrepancies between the results of plasma clearance and urinary clearance assessments were investigated by using an uncollimated gamma camera to measure the total retention of the tracer. RESULTS: Conventional slope-intercept calculations overestimated clearance compared with the new technique by more than 20% in 21% of the patients. Significant differences between the results of the two methods were more likely in patients with more severe ascites. Results of urine collection-based measurements of Cr-51 EDTA clearance were frequently significantly lower than measurements using the new technique, whereas measurements of urinary clearance of creatinine were higher. Gamma camera measurements suggest that discrepancies between total and urinary clearance of Cr-51 EDTA are due to incomplete urine collection. CONCLUSION: The new technique is a practical method for assessment of kidney function and should be used in patients with liver disease who have or may have ascites.

Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral administration.

This open-label, single-dose study assessed lenvatinib pharmacokinetics (PK) in subjects with normal hepatic function (n = 8) and mild, moderate, or severe hepatic impairment (n = 6 each). Subjects received 10 mg oral lenvatinib, except those with severe hepatic impairment (5 mg). Plasma and urine samples were collected over 14 days; free and total lenvatinib and its metabolites were analyzed using validated chromatography/spectrometry. PK parameters were estimated using noncompartmental analysis. There were no clinically meaningful effects of mild or moderate hepatic impairment on lenvatinib PK. Dose-normalized Cmax for free lenvatinib was 7.0, 3.7, 5.7, and 5.6 ng/mL in subjects with normal hepatic function, mild, moderate, and severe hepatic impairment, respectively. There was no consistent trend, although dose-normalized Cmax was lower for all subjects with hepatic impairment. AUCs increased 170% and t1/2 increased (37 versus 23 hours) in subjects with severe hepatic impairment. Changes in exposure based on total plasma concentrations were generally less than those based on free concentrations, suggesting changes in plasma protein binding in subjects with severe hepatic impairment. Lenvatinib was generally well tolerated. Subjects with severe hepatic impairment should begin lenvatinib treatment at a reduced dose of 14 mg versus 24 mg for subjects with normal liver function and subjects with mild or moderate hepatic impairment.