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Drug Metabolism and Disposition: the... Sep 2023Understanding the extended clearance concept and establishing a physiologically based pharmacokinetic (PBPK) model are crucial for investigating the impact of changes in... (Review)
Review
A 20-Year Research Overview: Quantitative Prediction of Hepatic Clearance Using the In Vitro-In Vivo Extrapolation Approach Based on Physiologically Based Pharmacokinetic Modeling and Extended Clearance Concept.
Understanding the extended clearance concept and establishing a physiologically based pharmacokinetic (PBPK) model are crucial for investigating the impact of changes in transporter and metabolizing enzyme abundance/functions on drug pharmacokinetics in blood and tissues. This mini-review provides an overview of the extended clearance concept and a PBPK model that includes transporter-mediated uptake processes in the liver. In general, complete in vitro and in vivo extrapolation (IVIVE) poses challenges due to missing factors that bridge the gap between in vitro and in vivo systems. By considering key in vitro parameters, we can capture in vivo pharmacokinetics, a strategy known as the top-down or middle-out approach. We present the latest progress, theory, and practice of the Cluster Gauss-Newton method, which is used for middle-out analyses. As examples of poor IVIVE, we discuss "albumin-mediated hepatic uptake" and "time-dependent inhibition" of OATP1Bs. The hepatic uptake of highly plasma-bound drugs is more efficient than what can be accounted for by their unbound concentration alone. This phenomenon is referred to as "albumin-mediated" hepatic uptake. IVIVE was improved by measuring hepatic uptake clearance in vitro in the presence of physiologic albumin concentrations. Lastly, we demonstrate the application of Cluster Gauss-Newton method-based analysis to the target-mediated drug disposition of bosentan. Incorporating saturable target binding and OATP1B-mediated hepatic uptake into the PBPK model enables the consideration of nonlinear kinetics across a wide dose range and the prediction of receptor occupancy over time. SIGNIFICANCE STATEMENT: There have been multiple instances where researchers' endeavors to unravel the underlying mechanism of poor in vitro-in vivo extrapolation have led to the discovery of previously undisclosed truths. These include 1) albumin-mediated hepatic uptake, 2) the target-mediated drug disposition in small molecules, and 3) the existence of a trans-inhibition mechanism by inhibitors for OATP1B-mediated hepatic uptake of drugs. Consequently, poor in vitro-in vivo extrapolation and the subsequent inquisitiveness of scientists may serve as a pivotal gateway to uncover hidden mechanisms.
Topics: Hepatocytes; Kinetics; Models, Biological; Liver; Albumins
PubMed: 37407092
DOI: 10.1124/dmd.123.001344 -
Expert Review of Gastroenterology &... Apr 2019Ascites commonly complicates cirrhosis, becoming refractory to treatment with diuretics and sodium restriction in approximately 10% of patients. Pathogenesis of... (Review)
Review
Ascites commonly complicates cirrhosis, becoming refractory to treatment with diuretics and sodium restriction in approximately 10% of patients. Pathogenesis of refractory ascites (RA) is multifactorial, the common final pathway being renal hypoperfusion and avid sodium retention. Refractory ascites has a negative prognostic implication in the natural history of cirrhosis. Management of RA include sodium restriction and regular large volume paracentesis (LVP) with albumin infusions, preventing paracentesis-induced circulatory dysfunction. In appropriate setting, transjugular intrahepatic porto-systemic shunt (TIPS) can be considered. Ascites clearance with TIPS can lead to nutritional improvement, avoiding sarcopenia. Liver transplantation (LT) remains the definitive treatment for eligible candidates. Areas covered: Our review summarizes current updates on pathogenesis and clinical management of RA including potential future therapeutic options such as the automated slow-flow ascites pump, chronic outpatient albumin infusion and cell-free and concentrated ascites reinfusion therapy. Expert commentary: Standard of care in patients with RA include LVP with albumin replacement and prompt referral for LT where indicated. Other novel therapeutic options on the horizon include automated low-flow ascites pump and cell-free, concentrated albumin reinfusion therapy.
Topics: Albumins; Ascites; Diet, Sodium-Restricted; Hemodynamics; Humans; Liver Cirrhosis; Liver Transplantation; Paracentesis; Peritoneovenous Shunt; Portasystemic Shunt, Transjugular Intrahepatic; Risk Factors; Splanchnic Circulation; Treatment Outcome
PubMed: 30791777
DOI: 10.1080/17474124.2018.1555469 -
Clinical Pharmacokinetics Jan 2018Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic... (Comparative Study)
Comparative Study Review
Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract the maximum concentration (C ), clearance (CL), and time of paclitaxel plasma concentration above 0.05 µmol/L (T > 0.05 µmol/L) following monotherapy of both the widely used cremophor-diluted paclitaxel and nanoparticle albumin-bound (nab-)paclitaxel. We identified a total of 53 studies yielding 121 aggregated pharmacokinetic profiles for paclitaxel monotherapy and extracted reported mean and median estimates of pharmacokinetic parameters. Paclitaxel has been studied formally at doses of 15-825 mg/m and infused over 0.5-96 h; included studies examined both weekly and every 3-weeks dosing cycles. The most widely used dose of cremophor-diluted paclitaxel, 175 mg/m given as a 3-h infusion, leads to an interstudy median C of 5.1 µmol/L [interquartile range (IQR) 4.5-5.7], CL of 12.0 L/h/m (IQR 10.9-12.9), and T > 0.05 µmol/L of 23.8 h (IQR 21.5-26.8). Importantly, the significant interindividual variation widely reported in the literature is not reflected in these interstudy estimates of pharmacokinetic parameters. Cremophor-diluted paclitaxel pharmacokinetics are non-linear following short (<6 h) but not long (>24 h) infusions. A similar pattern of non-linearity was observed for nab-paclitaxel, although the number of studies was limited. The pharmacokinetics of paclitaxel monotherapy have been widely studied at numerous dose levels of the Cremophor EL formulation, but are less well-characterized for the newer nab-paclitaxel formulation. In conclusion, paclitaxel pharmacokinetics are non-linear for short infusion times but not for longer infusions. Whether a similar conclusion can be drawn for nab-paclitaxel formulations requires further study.
Topics: Albumins; Antineoplastic Agents, Phytogenic; Dose-Response Relationship, Drug; Glycerol; Humans; Infusions, Intravenous; Neoplasms; Nonlinear Dynamics; Paclitaxel; Surface-Active Agents; Time Factors
PubMed: 28612269
DOI: 10.1007/s40262-017-0563-z -
Current Opinion in Chemical Biology Aug 2021The field of nuclear imaging and therapy is rapidly progressing with the development of targeted radiopharmaceuticals that show rapid targeting and rapid clearance with... (Review)
Review
The field of nuclear imaging and therapy is rapidly progressing with the development of targeted radiopharmaceuticals that show rapid targeting and rapid clearance with minimal background. Unfortunately, they are often reabsorbed in the kidneys, leading to possible nephrotoxicity, limiting the therapeutic dose, and/or reducing imaging quality. The blocking of endocytic receptors has been extensively used as a strategy to reduce kidney radiation. Alternatively, the physicochemical properties of radiotracers can be modulated to either prevent their reuptake or promote the excretion of radiometabolites. Other interesting strategies focus on the insertion of a cleavable linker between the radiolabel and the targeting moiety or pretargeting approaches in which the targeting moiety and radiolabel are administered separately. In the context of this review, we will discuss the latest advances and insights on strategies used to reduce renal retention of low- to moderate-molecular-weight radiopharmaceuticals.
Topics: Albumins; Animals; Contrast Media; Dose-Response Relationship, Radiation; Humans; Kidney; Molecular Weight; Radioisotopes; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography; Structure-Activity Relationship
PubMed: 34325089
DOI: 10.1016/j.cbpa.2021.06.008 -
Mediators of Inflammation 2019Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections... (Review)
Review
Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world's most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports-and is supported by-uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as "leaky gut." Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.
Topics: Albumins; Animals; Humans; Inflammation; Liver Cirrhosis; Macrophages; Reactive Oxygen Species
PubMed: 30930689
DOI: 10.1155/2019/7537649 -
Kidney360 Aug 2023HDF and MCO have shown greater clearance of middle-size uremic solutes in comparison with HF dialyzers; MCO has never been studied in HDF. MCO in HDF does not increase...
KEY POINTS
HDF and MCO have shown greater clearance of middle-size uremic solutes in comparison with HF dialyzers; MCO has never been studied in HDF. MCO in HDF does not increase the clearance of B2M and results in a higher loss of albumin.
BACKGROUND
Middle molecule removal and albumin loss have been studied in medium cutoff (MCO) membranes on hemodialysis (HD). It is unknown whether hemodiafiltration (HDF) with MCO membranes provides additional benefit. We aimed to compare the removal of small solutes and 2-microglobulin (B2M), albumin, and total proteins between MCO and high-flux (HFX) membranes with both HD and HDF, respectively.
METHODS
The cross-over study comprised 4 weeks, one each with postdilutional HDF using HFX (HFX-HDF), MCO (MCO-HDF), HD with HFX (HFX-HD), and MCO (MCO-HD). MCO and HFX differ with respect to several characteristics, including membrane composition, pore size distribution, and surface area (HFX, 2.5 m; MCO, 1.7 m). There were two study treatments per week, one after the long interdialytic interval and another midweek. Reduction ratios of vitamin B12, B2M, phosphate, uric acid, and urea corrected for hemoconcentration were computed. Dialysis albumin and total protein loss during the treatment were quantified from dialysate samples.
RESULTS
Twelve anuric patients were studied (six female patients; 44±19 years; dialysis vintage 35.2±28 months). The blood flow was 369±23 ml/min, dialysate flow was 495±61 ml/min, and ultrafiltration volume was 2.8±0.74 L. No significant differences were found regarding the removal of B2M, vitamin B12, and water-soluble solutes between dialytic modalities and dialyzers. Albumin and total protein loss were significantly higher in MCO groups than HFX groups when compared with the same modality. HDF groups had significantly higher albumin and total protein loss than HD groups when compared with the same dialyzer. MCO-HDF showed the highest protein loss among all groups.
CONCLUSIONS
MCO-HD is not superior to HFX-HD and HFX-HDF for both middle molecule and water-soluble solute removal. Protein loss was more pronounced with MCO when compared with HFX on both HD and HDF modalities. MCO-HDF has no additional benefits regarding better removal of B2M but resulted in greater protein loss than MCO-HD.
Topics: Cross-Over Studies; Hemodiafiltration; Renal Dialysis; Humans; Albumins
PubMed: 37651666
DOI: 10.34067/KID.0000000000000185 -
Annals of Hepatology 2024Hepatorenal syndrome (HRS) is a serious complication of cirrhosis treated with various medications. We aim to evaluate terlipressin and albumin's effectiveness and... (Meta-Analysis)
Meta-Analysis
INTRODUCTION AND OBJECTIVES
Hepatorenal syndrome (HRS) is a serious complication of cirrhosis treated with various medications. We aim to evaluate terlipressin and albumin's effectiveness and safety compared to albumin and noradrenaline in adult hepatorenal disease patients.
MATERIALS AND METHODS
Clinical trials from four databases were included. Cochrane's approach for calculating bias risk was utilized. We rated the quality evaluation by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). We included the following outcomes: serum creatinine (mg/dl), urine output (ml/24 h), mean arterial pressure (mmHg), reversal rate of HRS, mortality rate, blood plasma renin activity (ng/ml/h), plasma aldosterone concentration (pg/ml), urine sodium (mEq/l), and creatinine clearance (ml/min).
RESULTS
Our analysis of nine clinical studies revealed that the noradrenaline group was associated with higher creatinine clearance (MD = 4.22 [0.40, 8.05]), (P = 0.03). There were no significant differences in serum creatinine levels (MD = 0.03 [-0.07, 0.13]), urinary sodium (MD = -1.02 [-5.15, 3.11]), urine output (MD = 32.75 [-93.94, 159.44]), mean arterial pressure (MD = 1.40 [-1.17, 3.96]), plasma renin activity (MD = 1.35 [-0.17, 2.87]), plasma aldosterone concentration (MD = 55.35 [-24.59, 135.29]), reversal rate of HRS (RR = 1.15 [0.96, 1.37]), or mortality rate (RR = 0.87 [0.74, 1.01]) between the two groups (p-values > 0.05).
CONCLUSIONS
Noradrenaline is a safe alternative medical therapy for HRS.
Topics: Humans; Terlipressin; Hepatorenal Syndrome; Norepinephrine; Albumins; Treatment Outcome; Vasoconstrictor Agents; Adult; Creatinine; Lypressin
PubMed: 38460713
DOI: 10.1016/j.aohep.2024.101495 -
Giornale Italiano Di Nefrologia :... Aug 2022The evaluation of renal function is computed using the estimated glomerular filtration rate methods or the measured glomerular filtration rate. Cystatin C has been well...
The evaluation of renal function is computed using the estimated glomerular filtration rate methods or the measured glomerular filtration rate. Cystatin C has been well studied as marker of renal function compared to serum creatinine, but only few studies compare Glomerular Filtration Rates estimated including both creatinine and cystatin (eGFRcyst-crea) to creatinine clearance (CrCl). This cross-sectional study compares CrCl and eGFRcyst-crea with eGFRcrea and searches for correlation with comorbidities. This cross-sectional study consists of 78 patients hospitalized for acute and/or chronic renal disease. We performed the concordance correlation coefficient analysis between the eGFRcrea and the CrCl and eGFRcyst-crea in the whole sample and in the various subgroups. Steiger's comparison of correlations from dependent samples showed a correlation coefficient between C-reactive protein and eGFRcyst-crea stronger than between C-reactive protein and CrCl (Z: 2.51, p=0.012). Similar results were showed with the association with procalcitonin (Z: 5.24, p<0.001), serum potassium (Z: -3.13, p=0.002), and severe CKD (Z: -2.54, p=0.011). The concordance correlation coefficient test showed major differences between diagnostic methods compared to eGFR-crea in diabetic subgroup, severe CKD, and in procalcitonin higher than 0.5ng/ml. The demonstration of a strong concordance between the eGFRcrea and the eGFRcyst-crea allows us to diagnose and to stage CKD better than creatinine clearance in patients with high inflammatory status. Furthermore, this information opens new research scenarios, and further, larger studies are needed to confirm these hypotheses.
Topics: C-Reactive Protein; Creatinine; Cross-Sectional Studies; Humans; Procalcitonin; Renal Insufficiency, Chronic
PubMed: 36073332
DOI: No ID Found -
Kidney360 Jun 2023Albumin kinetics not only reflected the pathophysiology of minimal change nephrotic syndrome but was also a predictor of relapse. The high estimated 24-hour albumin...
KEY POINTS
Albumin kinetics not only reflected the pathophysiology of minimal change nephrotic syndrome but was also a predictor of relapse. The high estimated 24-hour albumin clearance predicts the minimal change nephrotic syndrome relapse. The 24-hour albumin clearance can easily be calculated from only serum albumin and urinary protein excretion, which are routine laboratory measurements.
BACKGROUND
Although albuminuria leakage that occurs in minimal change nephrotic syndrome (MCNS) may be related to the disease state, albumin kinetics in MCNS has never been evaluated. In this study, we investigated albumin kinetics in adult Japanese patients with MCNS by the estimated 24-hour albumin clearance (eC) and examined the association between eC and relapse.
METHODS
We retrospectively identified 103 adult patients with a histological diagnosis of MCNS from four hospitals in Japan (2010–2020). The primary outcome is the first relapse in 2 years after complete remission after corticosteroid therapy. The eC [l/min] was defined as (2.71828 [g/24 hours])/(serum albumin [g/dl]×1440 [min/24 hours]) for women and (2.71828 [g/24 hours])/(serum albumin [g/dl]×1440 [min/24 hours]) for men.
RESULTS
Relapse was observed in 44 patients (103 kidney biopsy samples; 42.7%). The mean patient age was 41.0 years. Patients had an eGFR of 71.0 ml/min per 1.73 m, urinary protein excretion of 6.8 g/d, serum albumin of 1.4 g/dl, and eC of 2.27 l/min. eC was strongly associated with hypoalbuminemia, severe proteinuria, lipid abnormalities, and coagulopathy. In the multivariable analysis, a high eC was significantly associated with relapse after adjusting for age, eGFR, time to complete remission, and urinary protein excretion (adjusted hazard ratio, 5.027; 95% confidence interval, 1.88 to 13.47; = 0.001).
CONCLUSIONS
This study revealed that eC, which could substitute albumin kinetics, reflected the severity of MCNS, and a high eC was associated with recurrence.
Topics: Humans; Nephrosis, Lipoid; Kidney Function Tests; Nephrotic Syndrome; Chronic Disease; Albumins; Recurrence
PubMed: 37166949
DOI: 10.34067/KID.0000000000000143 -
Critical Care (London, England) Dec 2021The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma... (Observational Study)
Observational Study
BACKGROUND
The measurement of circulating substrate concentrations does not provide information about substrate kinetics. It, therefore, remains unclear if a decrease in plasma concentration of albumin, as seen during critical illness, is a consequence of suppressed production in the liver or increased peripheral clearance. In this study, using stable isotope tracer infusions, we measured albumin and fibrinogen kinetics in septic patients and in a control group of non-septic subjects.
METHODS
With the approval from the institutional Research Ethics Board and after obtaining written informed consent from patients or their substitute decision maker, mechanically ventilated patients with sepsis and patients scheduled for elective coronary artery bypass grafting were enrolled. Patients in the non-sepsis group were studied on the day before surgery. The stable isotope L-[ring-H]phenylalanine was used to measure absolute synthesis rates (ASR) of albumin and fibrinogen. A priming dose of L-[ring-H]phenylalanine (4 µmol/kg) was given followed by a six-hour infusion at a rate of 0.15 µmol/kg/min. At baseline and hourly thereafter, blood was drawn to measure isotope enrichments by gas chromatography/mass spectrometry. Very low density lipoprotein apolipoprotein-B 100 isotopic enrichment was used to represent the isotopic enrichment of the phenylalanine precursor pool from which the liver synthesizes proteins. Plasma albumin and fibrinogen concentrations were also measured.
RESULTS
Mean plasma albumin in septic patients was decreased when compared to non-septic patients, while synthesis rates were comparable. Mean plasma fibrinogen and ASR in septic patients was increased when compared to non-septic patients. In non-septic patients, no statistically significant correlation between plasma albumin and ASR was observed but plasma fibrinogen significantly correlated with ASR. In septic patients, plasma albumin and fibrinogen significantly correlated with ASR.
CONCLUSIONS
While septic patients showed lower plasma albumin levels than non-septic patients, albumin synthesis was similar in the two groups suggesting that hypoalbuminemia during sepsis was not caused by suppressed hepatic production but a result of enhanced clearance from the circulation. Hyperfibrinogenemia in septic patients was a consequence of increased fibrinogen production.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT02865408 (registered on August 12, 2016) and ClinicalTrials.gov: NCT02549443 (registered on September 15, 2015).
Topics: Fibrinogen; Humans; Hypoalbuminemia; Kinetics; Sepsis; Serum Albumin
PubMed: 34920728
DOI: 10.1186/s13054-021-03860-7