Drug Clearance Research Articles

Optimal dosing regimen of biapenem based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation in patients with febrile neutropenia and haematological malignancies

In the current study, a population pharmacokinetic (PPK) model was developed for biapenem in patients with febrile neutropenia (FN) and haematological malignancies. Through Monte Carlo simulation, optimal administration regimens were suggested based on the developed PPK model. In a prospective, single-centre, open-label study, 174 plasma samples from 120 Chinese patients with FN and haematological malignancies were analysed by chromatography, and PK parameters were analysed by NONMEM. The drug clearance process was influenced by crucial covariates, namely creatinine clearance (CLCR) and concomitant posaconazole (POS). The ultimate PPK model was as follows: CL (L/h)=29.81×(CLCR/121.38)0.806×(1-POS×0.297); volume of distribution (L)=114. For the target of ≥40% fT>minimum inhibitory concentration (MIC) (duration that the plasma level exceeds the MIC of the causative pathogen) and achieving the probability of target attainment ≥90%, the PK/pharmacodynamic breakpoint was 2 mg/L for the 2.4 g/day dosing regimen consisting of 600 mg q6h and 800 mg q8h. The breakpoint was 1 mg/L for the 1.2 g/day dosing regimen consisting of 300 mg q6h and 600 mg q12h. Empirical therapy would benefit from utilizing higher dosages and extended infusion durations. Therefore, it is suggested that patients with symptoms that are strongly suggestive of Pseudomonas aeruginosa or Acinetobacter baumannii infection may be suitable for combined treatment with other antibacterial drugs.

Quantitative Prediction of OATP-Mediated Disposition and Biliary Clearance Using Human Liver Chimeric Mice.

Drug biliary clearance (CLbile) in vivo is among the most difficult pharmacokinetic parameters to predict accurately and quantitatively because biliary excretion is influenced by metabolic enzymes, transporters, and passive diffusion across hepatocyte membranes. The purpose of this study is to demonstrate the use of Hu-FRG mice [Fah-/-/Rag2-/-/Il2rg-/- (FRG) mice transplanted with human-derived hepatocytes] to quantitatively predict human organic anion transporting polypeptide (OATP)-mediated drug disposition and CLbile To predict OATP-mediated disposition, six OATP substrates (atorvastatin, fexofenadine, glibenclamide, pitavastatin, pravastatin, and rosuvastatin) were administered intravenously to Hu-FRG and Mu-FRG mice (FRG mice transplanted with mouse hepatocytes) with or without rifampicin as an OATP inhibitor. We calculated the hepatic intrinsic clearance (CLh,int) and the change of hepatic clearance (CLh) caused by rifampicin (CLh ratio). We compared the CLh,int of humans with that of Hu-FRG mice and the CLh ratio of humans with that of Hu-FRG and Mu-FRG mice. For predicting CLbile, 20 compounds (two cassette doses of 10 compounds) were administered intravenously to gallbladder-cannulated Hu-FRG and Mu-FRG mice. We evaluated the CLbile and investigated the correlation of human CLbile with that of Hu-FRG and Mu-FRG mice. We found good correlations between humans and Hu-FRG mice in CLh,int (100% within threefold) and CLh ratio (R2 = 0.94). Moreover, we observed a much better relationship between humans and Hu-FRG mice in CLbile (75% within threefold). Our results suggest that OATP-mediated disposition and CLbile can be predicted using Hu-FRG mice, making them a useful in vivo drug discovery tool for quantitatively predicting human liver disposition. SIGNIFICANCE STATEMENT: OATP-mediated disposition and biliary clearance of drugs are likely quantitatively predictable using Hu-FRG mice. The findings can enable the selection of better drug candidates and the development of more effective strategies for managing OATP-mediated DDIs in clinical studies.

Pharmacokinetics of Apixaban Among Peritoneal Dialysis Patients

The efficacy and safety profile of apixaban remains uncertain in patients receiving peritoneal dialysis (PD) despite increasing use in this population. Accordingly, we assessed the pharmacokinetics of apixaban among patients receiving PD. A pharmacokinetics study in a single center. Patients recruited received 1 week of apixaban at 2.5mg twice a day to reach steady state. Serial blood samples were then taken before and after the last dose for pharmacokinetics analysis of apixaban. Ten stable PD patients with atrial fibrillation in an outpatient setting. Pharmacokinetic parameters including the area under the concentration-time curve from time 0 to 12 hours after the last dose of apixaban (AUC0-12), peak concentration, trough level, time to peak apixaban concentration, half-life, and drug clearance were analyzed. There was a wide variation in the range of apixaban concentration across the 10 patients. The AUC0-12 for the PD group was significantly higher than those reported previously for hemodialysis patients or healthy individuals. Three patients had a supratherapeutic peak concentration whereas 2 patients had a supratherapeutic trough level as compared with the pharmacokinetic parameter in healthy individuals taking equivalent therapeutic dosage. Small sample size with short study duration limits the ability to ascertain the true bleeding risk and to detect any clinical outcomes. Results may be limited to Asian populations only. A proportion of PD patients had supratherapeutic levels even when the reduced dosage 2.5mg twice a day was used. Given the large interindividual variation in the drug level, therapeutic drug monitoring should be done if available. Otherwise, one should start the drug at reduced doses with caution and with more frequent clinical monitoring for any signs of bleeding.

A Systematic Review on Antimicrobial Pharmacokinetic Differences between Asian and Non-Asian Adult Populations.

While the relevance of inter-ethnic differences to the pharmacokinetic variabilities of antimicrobials has been reported in studies recruiting healthy subjects, differences in antimicrobial pharmacokinetics between Asian and non-Asian patients with severe pathologic conditions require further investigation. For the purpose of describing the potential differences in antimicrobial pharmacokinetics between Asian and non-Asian populations, a systematic review was performed using six journal databases and six theses/dissertation databases (PROSPERO record CRD42018090054). The pharmacokinetic data of healthy volunteers and non-critically ill and critically ill patients were reviewed. Thirty studies on meropenem, imipenem, doripenem, linezolid, and vancomycin were included in the final descriptive summaries. In studies recruiting hospitalised patients, inconsistent differences in the volume of distribution (Vd) and drug clearance (CL) of the studied antimicrobials between Asian and non-Asian patients were observed. Additionally, factors other than ethnicity, such as demographic (e.g., age) or clinical (e.g., sepsis) factors, were suggested to better characterise these pharmacokinetic differences. Inconsistent differences in pharmacokinetic parameters between Asian and non-Asian subjects/patients may suggest that ethnicity is not an important predictor to characterise interindividual pharmacokinetic differences between meropenem, imipenem, doripenem, linezolid, and vancomycin. Therefore, the dosing regimens of these antimicrobials should be adjusted according to patients' demographic or clinical characteristics that can better describe pharmacokinetic differences.

Complex PK-PD of an engineered IL-15/IL-15Rα–Fc fusion protein in cynomolgus monkeys: QSP modeling of lymphocyte dynamics

XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment. XmAb24306 contains mutations in IL-15 that attenuate its affinity to the heterodimeric IL-15 receptor βγ (IL-15R). We observe substantially prolonged pharmacokinetics (PK) (half-life ∼ 2.5 to 4.5 days) in single- and repeat-dose cynomolgus monkey (cyno) studies compared to wild-type IL-15 (half-life ∼ 1 hour), leading to increased exposure and enhanced and durable expansion of NK cells, CD8+ T cells and CD4–CD8– (double negative [DN]) T cells. Drug clearance varied with dose level and time post-dose, and PK exposure decreased upon repeated dosing, which we attribute to increased target-mediated drug disposition (TMDD) resulting from drug-induced lymphocyte expansion (i.e., pharmacodynamic (PD)-enhanced TMDD). We developed a quantitative systems pharmacology (QSP) model to quantify the complex PKPD behaviors due to the interactions of XmAb24306 with multiple cell types (CD8+, CD4+, DN T cells, and NK cells) in the peripheral blood (PB) and lymphoid tissues. The model, which includes nonspecific drug clearance, binding to and TMDD by IL15R differentially expressed on lymphocyte subsets, and resultant lymphocyte margination/migration out of PB, expansion in lymphoid tissues, and redistribution to the blood, successfully describes the systemic PK and lymphocyte kinetics observed in the cyno studies. Results suggest that after 3 doses of every-two-week (Q2W) doses up to 70 days, the relative contributions of each elimination pathway to XmAb24306 clearance are: DN T cells > NK cells > CD8+ T cells > nonspecific clearance > CD4+ T cells. Modeling suggests that observed cellular expansion in blood results from the influx of cells expanded by the drug in lymphoid tissues. The model is used to predict lymphoid tissue expansion and to simulate PK-PD for different dose regimens. Thus, the model provides insight into the mechanisms underlying the observed PK-PD behavior of an engineered cytokine and can serve as a framework for the rapid integration and analysis of data that emerges from ongoing clinical studies in cancer patients as single-agent or given in combination.

The Optimal Dosing Regimen of Super Bioavailable Itraconazole in Obesity: An Experimental Rat Model Study.

Background Obesity may alter tissue distribution and clearance of several drugs, especially lipophilic ones. Itraconazole, a lipophilic drug, has been recently introduced in a super-bioavailable formulation (SB-ITZ) for the treatment of dermatophytosis. Evidence regarding optimal dosing of SB-ITZ in obesity is lacking. A current experimental study was planned to analyze tissue concentrations of SB-ITZ at different doses in obese and non-obese rats. Materials and methods Thirty-six Wistar albino rats of either sex were divided into obese and non-obese rats equally. Further, rats in both categories were divided into three dosing groups. Group 1 received SB-ITZ 13 mg once daily in the morning, group 2 received SB-ITZ 13 mg in the morning and 6.5 mg in the evening, while Group 3 rats received SB-ITZ 13 mg twice daily, orally. Concentrations of SB-ITZ in the skin, serum, and fatty tissue were assessed in each group on days 7, 14, 21, and 28. Comparison of SB-ITZ concentrations in various tissues in obese and non-obese rats and inter-group comparison of tissue concentrations across the three dosing regimens was done at day 28 and expressed as Mean ± SD.36 Wistar rats were divided into obese and non-obese rats equally. Results At day 28, skin concentrations of SB-ITZ were 5.36±1.1, 8.9±1.7 and 10.13±1.7 µg/g in Groups 1, 2, and 3, respectively, in non-obese rats, which was statistically significant (p<0.05) than skin concentration of obese rats (2.72±0.6, 4.2±0.7 and 4.66±0.5 µg/g) for the corresponding dosing groups respectively. Skin concentration of SB-ITZ was statistically significant for Groups 2 and 3 as compared to Group 1. Still, no statistically significant difference was noted between Groups 2 and 3 in non-obese and obese rats. Fatty tissue concentration of SB-ITZ was comparable in all 3 dosing regimens in non-obese and obese rats. But on the intergroup comparison, a statistically significant difference was observed for Groups 2 and 3 against Group 1 (p<0.05). Increasing the dose of SB-ITZ increased serum concentration. In non-obese rats, a statistically significant difference was noted between Group 2 (74.33±6.6 ng/ml) and Group 1 (52.5±9.9 ng/ml); p<0.01 and also in Group 3 (81.33±6.8 ng/ml) against Group 1; p<0.01. Group 3 achieved significantly higher concentration than the other two groups in obese rats (Group 3; 72±5.3, Group 2; 60.5±4.3, and Group 1; 45±7 ng/ml; p<0.01). Conclusion Overall, skin, fatty tissue, and serum concentrations of SB-ITZ were higher in non-obese rats compared to obese rats in all three dosing groups. Moreover, skin and fatty tissue concentrations were proportionately higher than serum in all the groups in non-obese and obese rats. Though the skin concentration of non-obese rats was significantly higher than obese rats, skin concentration in obese rats was within the minimum inhibitory concentration (MIC) range, demonstrating the efficacy of all dosing regimens.

The Uses and Advantages of Kirchhoff’s Laws vs. Differential Equations in Pharmacology, Pharmacokinetics, and (Even) Chemistry

In chemistry, rate processes are defined in terms of rate constants, with units of time−1, and are derived by differential equations from amounts. In contrast, when considering drug concentrations in biological systems, particularly in humans, rate processes must be defined in terms of clearance, with units of volume/time, since biological volumes, which are highly dependent on drug partition into biological tissues, cannot be easily determined. In pharmacology, pharmacokinetics, and in making drug dosing decisions, drug clearance and changes in drug clearance are paramount. Clearance is defined as the amount of drug eliminated or moved divided by the exposure driving that elimination or movement. Historically, all clearance derivations in pharmacology and pharmacokinetics have been based on the use of differential equations in terms of rate constants and amounts, which are then converted into clearance equations when multiplied/divided by a hypothesized volume of distribution. Here, we show that except for iv bolus dosing, multiple volumes may be relevant. We have recently shown that clearance relationships, as well as rate constant relationships, may be derived independent of differential equations using Kirchhoff’s Laws from physics. Kirchhoff’s Laws may be simply translated to recognize that when two or more rate-defining processes operate in parallel, the total value of the overall reaction parameter is equal to the sum of those rate-defining processes. In contrast, when two or more rate-defining processes operate in series, the inverse of the total reaction parameter is equal to the sum of the inverse of those rate-defining steps.Graphical

Pharmacokinetic relevance of glomerular hyperfiltration for drug dosing.

In chronic kidney disease (CKD) patients, hypofiltration may lead to the accumulation of drugs that are cleared mainly by the kidney and, vice versa, hyperfiltration may cause augmented renal excretion of the same drugs. In this review we mainly focus on the issue of whether hyperfiltration significantly impacts the renal clearance of drugs and whether the same alteration may demand an up-titration of the doses applied in clinical practice. About half of severely ill, septic patients and patients with burns show glomerular hyperfiltration and this may lead to enhanced removal of drugs such as hydrophilic antibiotics and a higher risk of antibiotic treatment failure. In general, hyperfiltering obese individuals show higher absolute drug clearances than non-obese control subjects, but this depends on the body size descriptor adopted to adjust for fat excess. Several mechanisms influence pharmacokinetics in type 2 diabetes, including renal hyperfiltration, reduced tubular reabsorption and augmented tubular excretion. However, no consistent pharmacokinetic alteration has been identified in hyperfiltering obese subjects and type 2 diabetics. Non-vitamin K antagonist oral anticoagulants (NOACs) have exhibited lower plasma concentrations in hyperfiltering patients in some studies in patients with atrial fibrillation, but a recent systematic review failed to document any excess risk for stroke and systemic embolism in these patients. Hyperfiltration is common among severely ill patients in intensive care units and drug levels should be measured whenever possible in these high-risk patients to prevent underdosing and treatment failure. Hyperfiltration is also common in patients with obesity or type 2 diabetes, but no consistent pharmacokinetic alteration has been described in these patients. No NOAC dose adjustment is indicated in patients with atrial fibrillation being treated with these drugs.

Predicting the Effect of Renal Function on Systemic Clearance: Is a Simple Scaling Method Sufficient?

PurposeTo employ a simple scaling method to predict systemic or oral clearance for drugs that are primarily renally cleared knowing the fraction eliminated in urine (fe) and a patient's renal function relative to healthy controls (SGFR). MethodsObservations evaluating drug clearance as a function of creatinine clearance for renally cleared drugs (fe >0.3) were obtained from literature sources. The analysis comprised of 82 unique drugs from 124 studies including 31 drugs with replicate studies. A simple scaler for renal function was employed and compared to the linear regression of available data. For drugs in which replicate studies were available, the ability of the linear regression (Cl vs ClCR) from one pharmacokinetic study was used to predict observations from an assigned replicate and compared to the scaling approach. ResultsFor patients categorized as severe kidney disease (ClCR fixed at 20 ml/min), the scalar tended to over predict some observations, but 92% of the predictions were within 50–200% of the observed data. For drugs with available replicates, the scalar was as good or better in predicting the influence of ClCR on systemic clearance from a separate study when comparing against the linear regression approach. ConclusionA scaling approach to account for alterations in drug clearance appears to have its advantages and represents a simple and generalizable method for guiding dose adjustments in patients with decreased renal function for drugs that are renally cleared (fe >0.3). In addition to its use in clinical practice, validation of this approach may have implications in facilitating more efficient drug development processes for designing dose-adjusted pharmacokinetic studies in patients with renal disease.

Inactivation of Human Aldehyde Oxidase by Small Sulfhydryl-containing Reducing Agents.

Human aldehyde oxidase (hAOX1) is a molybdoflavoenzyme that belongs to the xanthine oxidase (XO) family. hAOX1 is involved in phase I drug metabolism, but its physiological role is not fully understood to date and preclinical studies consistently underestimated hAOX1 clearance. In the present work, we report an unexpected effect of the common sulfhydryl-containing reducing agents, e.g. dithiothreitol (DTT), on the activity of hAOX1 and mouse aldehyde oxidases. We demonstrate that this effect is due to the reactivity of the sulfido ligand bound at the molybdenum cofactor (Moco) with the sulfhydryl groups. The sulfido ligand coordinated to the Mo atom in the XO family of enzymes plays a crucial role in the catalytic cycle and its removal results in the total inactivation of these enzymes. Since liver cytosols, S9 fractions and hepatocytes are commonly used to screen the drug candidates for hAOX1, our study suggests that DTT treatment of these samples should be avoided, as otherwise false negative results by an inactivated hAOX1 might be obtained. Significance Statement This work characterizes the inactivation of human aldehyde oxidase (hAOX1) by sulfhydryl-containing agents and identifies the site of inactivation. The role of DTT in the inhibition of hAOX1 should be considered for the preparation of hAOX1-containing fractions for pharmacological studies on drug metabolism and drug clearance.

Effects of Mouse Kidney Parvovirus on Pharmacokinetics of Chemotherapeutics and the Adenine Model of Chronic Kidney Disease.

Mouse kidney parvovirus (MKPV) causes inclusion body nephropathy in severely immunocompromised mice and renal interstitial inflammation in immunocompetent mice. Here we sought to determine the effects of MKPV on pre-clinical murine models that depend on renal function. To assess the effects of MKPV infection on the pharmacokinetics of 2 renally excreted chemotherapeutic agents, methotrexate and lenalidomide, we measured drug concentrations in the blood and urine of MKPV-infected or uninfected immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and immunocompetent C57BL/6NCrl (B6) female mice. No differences in plasma pharmacokinetics were observed for lenalidomide. However, the AUC of methotrexate was 1.5-fold higher in uninfected NSG mice compared with infected NSG mice, 1.9-fold higher in infected B6 mice compared with uninfected B6 mice, and 4.3-fold higher in uninfected NSG mice compared with uninfected B6 mice. MKPV infection did not significantly affect the renal clearance of either drug. To assess effects of MKPV infection on the adenine diet model of chronic kidney disease, MKPV-infected and uninfected B6 female mice were fed a 0.2% adenine diet, and clinical and histopathologic features of disease were assessed over 8 wk. MKPV infection did not significantly alter urine chemistry results, hemogram findings, or serum concentrations of BUN, creatinine, or symmetric dimethylarginine. However, infection did influence histologic outcomes. As compared with uninfected mice, MKPV-infected mice had more interstitial lymphoplasmacytic infiltrates after 4 and 8 wk of diet consumption and less interstitial fibrosis at week 8. Macrophage infiltrates and renal tubular injury were similar between in infected and uninfected mice. These findings indicate that MKPV infection had minimal effects on the renal excretion of 2 chemotherapeutics and on serum biomarkers of renal function. However, infection significantly influenced two histologic features of the adenine diet model of chronic renal disease. MKPV-free mice are critically important in studies evaluating renal histology as an experimental outcome.

Intra-articular nanoparticles based therapies for osteoarthritis and rheumatoid arthritis management.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic and progressive inflammatory joint diseases that affect a large population worldwide. Intra-articular administration of various therapeutics is applied to alleviate pain, prevent further progression, and promote cartilage regeneration and bone remodeling in both OA and RA. However, the effectiveness of intra-articular injection with traditional drugs is uncertain and controversial due to issues such as rapid drug clearance and the barrier afforded by the dense structure of cartilage. Nanoparticles can improve the efficacy of intra-articular injection by facilitating controlled drug release, prolonged retention time, and enhanced penetration into joint tissue. This review systematically summarizes nanoparticle-based therapies for OA and RA management. Firstly, we explore the interaction between nanoparticles and joints, including articular fluids and cells. This is followed by a comprehensive analysis of current nanoparticles designed for OA/RA, divided into two categories based on therapeutic mechanisms: direct therapeutic nanoparticles and nanoparticles-based drug delivery systems. We highlight nanoparticle design for tissue/cell targeting and controlled drug release before discussing challenges of nanoparticle-based therapies for efficient OA and RA treatment and their future clinical translation. We anticipate that rationally designed local injection of nanoparticles will be more effective, convenient, and safer than the current therapeutic approach.

A uniquein vivopharmacokinetic profile,in vitrometabolic stability and hepatic first-pass metabolism of garcinol, a promising novel anticancer phytoconstituent, by liquid chromatography–mass spectrometry

AbstractObjectivesGarcinol exhibits promising potential anticancer activity in cancer cells by inhibiting several critical regulatory pathways. Despite its pharmacological activity, information regarding its pharmacokinetics and metabolism is unavailable. Hence, we aimed to systematically determine the in vivo pharmacokinetic parameters, in vitro metabolic stability and hepatic first-pass metabolism of garcinol.MethodsWe developed and validated a sensitive bioanalytical method for the quantitative determination of garcinol in rat plasma and human liver microsomes using liquid chromatography–tandem mass spectrometry (LC–MS/MS). The developed method was applied to assess the pharmacokinetic parameters, bioavailability and metabolic stability associated with metabolic half-life and intrinsic hepatic clearance. Further, we calculated the hepatic first-pass metabolism of garcinol from the metabolic stability data.Key findingsThe metabolic stability of garcinol in human liver microsomes demonstrated it as a medium clearance drug with a CLint value of 33.94 µL/min/mg microsomal protein and 94% of garcinol would escape the hepatic first-pass metabolism. Furthermore, a pharmacokinetics study of garcinol in Sprague Dawley rats showed 26.64 ± 0.23% and 35.72 ± 0.97% oral bioavailability at two doses, that is 22.5 and 45 mg/kg, respectively. The Cmax values at these two oral doses were 2317.69 ± 180.44 and 3446.14 ± 190.12 ng/mL.ConclusionsMetabolic stability data showed that garcinol is a medium clearance drug and less fraction of the drug undergoes hepatic first-pass metabolism. The determined pharmacokinetic parameters and metabolic stability data help to understand and optimise the dose and route of administration for designing clinical trials to further develop garcinol as an anticancer drug.

VEDOLIZUMAB, USTEKINUMAB AND TOFACITINIB AS TRIPLE THERAPY FOR ULCERATIVE COLITIS

Therapies for ulcerative colitis include mesalamine, immunomodulators, biologics, and small molecules. Unfortunately, patient response is not universal, and efficacy can diminish with time, postulated to be from increased drug clearance, anti-drug antibodies with biologics, and immune mediated pathogenesis changes. Biologic combinations have been investigated for producing synergistic drug effects and extending targeted therapy in patients lacking monotherapy response, with promise shown in two drug combinations (1), but not investigated using three.

Effect of flowing water on the pharmacokinetic properties of norfloxacin in channel catfish (Ictalurus punctatus) after single-dose oral administration.

The recirculating aquaculture system (RAS) is a widely used, water-saving and efficient aquaculture model. However, bacterial diseases are common in farmed fish reared at high densities. Although antibiotics effectively treat these diseases, developing efficient methods to increase drug clearance in fish and decrease the concentrations of antibiotic residues in aquatic products is essential. This study evaluates the effect of flowing water in the RAS on norfloxacin (NOR) pharmacokinetics in channel catfish (Ictalurus punctatus). Channel catfish were randomly divided into the control group (RAS group) and the experimental group (flow-through aquaculture system group) (120 individuals/group). A NOR dose of 20mg/kg was then orally administered to the fish. Plasma, muscle, liver and kidney samples were collected up to 168 h after treatment. NOR concentrations were measured using liquid chromatography-mass spectrometry, and pharmacokinetic parameters were calculated using a non-compartmental method. Flowing water had a significant effect on the plasma pharmacokinetics and tissue distribution of NOR, increasing NOR clearance in the kidney, muscle and plasma. The time to maximum concentration of NOR was shorter in the plasma and longer in the kidney and liver. Moreover, flowing water increased the maximum concentration of NOR in the kidney, muscle and plasma and decreased the area under the concentration-time curve from time 0 to the last measurable concentration in the liver and plasma. Flowing water decreased the withdrawal period in muscle from 10 to 6 days. These results indicate that flowing water can potentially increase NOR clearance in channel catfish.

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies

In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.

Development of a Supramolecular Hydrogel for Intraperitoneal Injections.

Local intraperitoneal drug administration is considered a challenging drug delivery route. The therapeutic efficiency is low, mainly due to rapid clearance of drugs. To increase the intraperitoneal retention time of specific drugs, a pH-sensitive supramolecular hydrogel that can act as a drug delivery vehicle is developed. To establish the optimal formulation of the hydrogel and to study its feasibility, safety, and tissue compatibility, in vitro, postmortem, and in vivo experiments areperformed. In vitro tests reveal that a hydrogelator formulation with pH ≥ 9 results in a constant viscosity of 0.1 Pa·s. After administration postmortem, the hydrogel covers the parietal and visceral peritoneum with a thin, soft layer. In the subsequent in vivo experiments, 14 healthy rats are subjected to intraperitoneal injection with the hydrogel. Fourteen and 28 days after implantation, the animals are euthanized. Intraperitoneal exposure to the hydrogel is not resulted in significant weight loss or discomfort. Moreover, no macroscopic adverse effects or signs of organ damage are detected. In several intra-abdominal tissues, vacuolated macrophages are found indicating a physiological degradation of the synthetic hydrogel. This study demonstrates that the supramolecular hydrogel is safe for intraperitoneal application and that the hydrogel shows good tissue compatibility in rats.

Head-to-tail imaging of mice with spiral volumetric optoacoustic tomography

Optoacoustic tomography has been established as a powerful modality for preclinical imaging. However, efficient whole-body imaging coverage has not been achieved owing to the arduous requirement for continuous acoustic coupling around the animal. In this work, we introduce panoramic (3600) head-to-tail 3D imaging of mice with spiral volumetric optoacoustic tomography (SVOT). The system combines multi-beam illumination and a dedicated head holder enabling uninterrupted acoustic coupling for whole-body scans. Image fidelity is optimized with self-gated respiratory motion rejection and dual speed-of-sound reconstruction algorithms to attain spatial resolution down to 90 µm. The developed system is thus highly suitable for visualizing rapid biodynamics across scales, such as hemodynamic changes in individual organs, responses to treatments and stimuli, perfusion, total body accumulation, or clearance of molecular agents and drugs with unmatched contrast, spatial and temporal resolution.

Gut microbiota and host cytochrome P450 characteristics in the pseudo germ-free model: co-contributors to a diverse metabolic landscape

BackgroundThe pseudo germ-free (PGF) model has been widely used to research the role of intestinal microbiota in drug metabolism and efficacy, while the modelling methods and the utilization of the PGF model are still not standardized and unified. A comprehensive and systematic research of the PGF model on the composition and function of the intestinal microbiota, changes in host cytochrome P450 (CYP450) enzymes expression and intestinal mucosal permeability in four different modelling cycles of the PGF groups are provided in this paper.Results16S rRNA gene amplicon sequencing was employed to compare and analyze the alpha and beta diversity, taxonomic composition, taxonomic indicators and predicted function of gut microbiota in the control and PGF groups. Bacterial richness and diversity decreased significantly in the PGF group beginning after the first week of establishment of the PGF model with antibiotic exposure. The PGF group exposed to antibiotics for 4-week-modelling possessed the fewest indicator genera. Moreover, increased intestinal mucosal permeability occurred in the second week of PGF model establishment, indicating that one week of antibiotic exposure is an appropriate time to establish the PGF model. The results of immunoblots revealed that CYP1A2, CYP2C19 and CYP2E1 expression was significantly upregulated in the PGF group compared with the control group, implying that the metabolic clearance of related drugs would change accordingly. The abundance of functional pathways predicted in the gut microbiota changed dramatically between the control and PGF groups.ConclusionsThis study provides information concerning the microbial and CYP450 enzyme expression profiles as a reference for evaluating drug metabolism differences co-affected by gut microbiota and host CYP450 enzymes in the PGF model.

Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis.

Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.