Plasma Protein Binding Research Articles

Plasma Protein Adsorption on Melphalan Prodrug Bearing Liposomes - Bare, Stealth, and Targeted

Background: Plasma protein binding is inevitable for nanomaterials injected into blood circulation. For liposomes, this process is affected by the lipid composition of the bilayer. Membrane constituents and their ratio define liposome characteristics, namely, surface charge and hydrophobicity, which drive protein adsorption. Roughly 30 years ago, the correlation between the amount of bound proteins and the resulting circulation time of liposomes was established by S. Semple, A. Chonn, and P. Cullis. Here, we have estimated ex vivo plasma protein binding, primarily to determine the impact of melphalan prodrug inclusion into bilayer on bare, PEGylated (stealth), and Sialyl Lewis X (SiaLeX)-decorated liposomes. Experimental: Liposomes were allowed to bind plasma proteins for 15 minutes, then liposome-protein complexes were isolated, and protein and lipid quantities were assessed in the complexes. In addition, the uptake by activated HUVEC cells was evaluated for SiaLeX-decorated liposomes. Results:: Melphalan moieties on the bilayer surface enrich protein adsorption compared to pure phosphatidylcholine sample. Although PEG-lipid had facilitated a significant decrease in protein adsorption in the control sample, when prodrug was added to the composition, the degree of pro-tein binding was restored to the level of melphalan liposomes without a stealth barrier. A similar effect was observed for SiaLeX-decorated liposomes. Conclusion: None of the compositions reported here should suffer from quick elimination from circulation, according to the cut-off values introduced by Cullis and colleagues. Nevertheless, the amount of bound proteins is sufficient to affect biodistribution, namely, to impair receptor recog-nition of SiaLeX and reduce liposome uptake by endothelial cells.

Insights into interspecies protein binding variability using clindamycin as an example

Abstract Background In the preclinical development of new drugs, animal models are often employed to predict their efficacy in humans, relying on translational pharmacokinetic/pharmacodynamic (PK/PD) studies. We performed in vitro experiments focusing on the comparison of plasma protein binding (PPB) and bacterial growth dynamics of clindamycin, a commonly used antimicrobial agent, across a range of drug concentrations and plasma environments. Methods Human, bovine and rat plasma were used for determining PPB of clindamycin at various antibiotic concentrations in buffer and media containing 20% to 70% plasma or pure plasma using ultrafiltration (UF) and equilibrium dialysis (ED). Also bacterial growth and time–kill assays were performed in Mueller–Hinton broth (MHB) containing various percentages of plasma. Results Protein binding of clindamycin correlated well between UF and ED. Notably, clindamycin exhibited substantially lower protein binding to rat plasma compared with human and bovine plasma. Staphylococcus aureus growth was significantly reduced in 70% human, bovine, and rat plasma after 4, 8 and 24 h compared with standard MHB. Time–kill data demonstrated that bacterial counts at both 20% and 70% plasmas were less when compared with MHB at drug concentrations lower than MIC after 4 and 8 h of incubation. For rat plasma, the difference was maintained over 24 h of incubation. Furthermore, a complete bacterial killing at 16 mg/L was observed after 24 h in 20% and 70% human and bovine plasma, but not for rat plasma. Conclusions Recognizing interspecies differences in PB might be essential for optimizing the translational relevance of preclinical studies.

Characterization of Nonclinical Drug Metabolism and Pharmacokinetic Properties of Phosphorodiamidate Morpholino Oligonucleotides, a Novel Drug Class for Duchenne Muscular Dystrophy.

Eteplirsen, golodirsen, and casimersen are phosphorodiamidate morpholino oligomers (PMOs) that are approved in the United States for the treatment of patients with Duchenne muscular dystrophy (DMD) with mutations in the DMD gene that are amenable to exon 51, 53, and 45 skipping, respectively. Here we report a series of in vivo and in vitro studies characterizing the drug metabolism and pharmacokinetic (DMPK) properties of these three PMOs. Following a single intravenous dose, plasma exposure was consistent for all three PMOs in mouse, rat, and nonhuman primate (NHP), and plasma half-lives were similar for eteplirsen (2.0-4.1 h) and golodirsen (2.1-8.7 h) across species and more variable for casimersen (3.2-18.1 h). Plasma protein binding was low (<40%) for all three PMOs in mouse, rat, NHP, and human and was largely concentration independent. In the mdx mouse model of DMD, following a single intravenous injection, extensive biodistribution was observed in the target skeletal muscle tissues and the kidney for all three PMOs; consistent with the latter finding, the predominant route of elimination was renal. In vitro studies using liver microsomes showed no evidence of hepatic metabolism, and none of the PMOs were identified as inhibitors or inducers of the human cytochrome P450 enzymes or membrane drug transporters tested at clinically relevant concentrations. These findings suggest that key DMPK features are consistent for eteplirsen, golodirsen, and casimersen and provide evidence for the concept of a PMO drug class with potential application to novel exon-skipping drug candidates. SIGNIFICANCE STATEMENT: The PMOs eteplirsen, golodirsen, and casimersen share similar absorption, distribution, metabolism, and excretion and DMPK properties, which provides evidence for the concept of a PMO treatment class. A PMO drug class may support a platform approach to enhance understanding of the pharmacokinetic and pharmacodynamic behavior of these molecules. The grouping of novel agent series into platforms could be beneficial in the development of drug candidates for populations in which traditional clinical trials are not feasible.

Cleavable Novel Thienopyridine Derivatives as Potent Antithrombotic Agents

AbstractThienopyridine derivatives are specifically designed for utilization in antithrombotic therapy to help combat cardiovascular disorders linked to thrombosis. This study introduces new thienopyridine derivatives with superior therapeutic efficacy through synergies by dual functional compounds, developed as antithrombotic agents. Through computational design, we discovered 32 compounds out of a library of 100 compounds that exhibit efficacy. The compounds are synthesized by multiple steps and subsequently purified using chromatographic procedures to achieve a purity level of &gt;99%. Using the ADP‐induced platelet aggregation assay, we have found 4 active test compounds (ACG‐0173‐19, ACG‐0173‐37, ACG‐A‐04, and ACG‐B‐03) out of a total of 32 compounds. On the other hand, ACG‐0173‐19, ACG‐0173‐37, ACG‐A‐04, and ACG‐B‐03 have demonstrated the highest percentage activity on factor Xa (FXa) inhibition. The ACG‐A‐04 chemical exhibited the highest hydrophilicity, specifically in terms of its aqueous solubility. It had a solubility of 0.44 mg/mL in pH 5.8, 0.29 mg/L in pH 6.2, and 0.145 mg/L in pH 7.4 buffers. In comparison, the standards APX‐01 (apixaban) and PRG‐01(prasugrel) had lower hydrophilicity. Based on cytotoxicity investigations, it was determined that the test substances do not exhibit harmful effects. The results indicated that the test chemicals can undergo hydrolysis in blood plasma rather than in other organs. Among the four test drugs, ACG‐1073‐19 exhibited an unbound fraction of 44.1%, which is twice as high as the standards (apixaban). ACG‐1073‐37 demonstrates superior plasma protein binding (33.2%) compared to all other test compounds. The compounds resulted in a higher expression of CD61, CD42b, and CD62P in platelets compared to the control. The ACG‐1073‐37 molecule had a Caco‐2 permeability of 51%, which is extremely close to the Caco‐2 permeability of the control medicines (55% for APX‐01 and 62% for PRG‐01). Through the assessment of microsomal stability, it was determined that ACG‐1073‐37 and ACG‐A‐04 exhibited metabolic stability for 42.4 and 34.14 min, respectively.

Identification of fibrinogen as a plasma protein binding partner for lecanemab biosimilar IgG.

Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, lecanemab administered as a bi-monthly infusion (typically 10 mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study, we investigated potential plasma protein binding (PPB) interaction to lecanemab using lecanemab biosimilar. Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions of human plasma obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate plasma binders was confirmed by western blotting, ELISA, and surface plasmon resonance analysis. Using a combination of equilibrium dialysis, ELISA, and western blotting in human plasma, we first describe the presence of likely PPB partners to lecanemab biosimilar and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that PPB may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

The state-of-the-art machine learning model for plasma protein binding prediction: Computational modeling with OCHEM and experimental validation

Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Existing models for predicting PPB often suffer from low prediction accuracy and poor interpretability, especially for high PPB compounds, and are most often not experimentally validated. Here, we carried out a strict data curation protocol, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model (available on the OCHEM platform https://ochem.eu/article/29) was further retrospectively validated for a set of 63 poly-fluorinated molecules and prospectively validated for a set of 25 highly diverse compounds, and its performance for both these sets was superior to that of the other previously reported models. Furthermore, we identified the physicochemical and structural characteristics of high and low PPB molecules for further structural optimization. Finally, we provide practical and detailed recommendations for structural optimization to decrease PPB binding of lead compounds.

Changes in Plasma Clearance of CYP450 Probe Drugs May Not be Specific for Altered In Vivo Enzyme Activity Under (Patho)Physiological Conditions: How to Interpret Findings of Probe Cocktail Studies.

CYP450 (CYP) phenotyping involves quantifying an individual's plasma clearance of CYP-specific probe drugs, as a proxy for in vivo CYP enzyme activity. It is increasingly applied to study alterations in CYP enzyme activity under various (patho)physiological conditions, such as inflammation, obesity, or pregnancy. The phenotyping approach assumes that changes in plasma clearance of probe drugs are driven by changes in CYP enzyme activity. However, plasma clearance is also influenced by protein binding, blood-to-plasma ratio, and hepatic blood flow, all of which may change under (patho)physiological conditions. Using a physiologically based pharmacokinetic (PBPK) workflow, we aimed to evaluate whether the plasma clearance of commonly used CYP probe drugs is indeed directly proportional to alterations in CYP enzyme activity (sensitivity), and to what extent alterations in protein binding, blood-to-plasma ratio, and hepatic blood flow observed under (patho)physiological conditions impact plasma clearance (specificity). Plasma clearance of CYP probe drugs is sensitive to alterations in CYP enzyme activity, since alterations in intrinsic clearance between - 90% and + 150% resulted in near-proportional changes in plasma clearance, except for midazolam in the case of > 50% CYP3A4 induction. However, plasma clearance also changed near-proportionally with alterations in the unbound drug fraction, diminishing probe specificity. This was particularly relevant for high protein-bound probe drugs, as alterations in plasma protein binding resulted in larger relative changes in the unbound drug fraction. Alterations in the blood-to-plasma ratio and hepatic blood flow of ± 50% resulted in plasma clearance changes of less than ± 16%, meaning they limitedly impacted plasma clearance of CYP probe drugs, except for midazolam. In order to correct for the impact of non-metabolic determinants on probe drug plasma clearance, an R script was developed to calculate how much the CYP enzyme activity is actually altered under (patho)physiological conditions, when alterations in the unbound drug fraction, blood-to-plasma ratio, and/or hepatic blood flow also impact probe drug plasma clearance. As plasma protein binding can change under (patho)physiological conditions, alterations in unbound drug fraction should be accounted for when using CYP probe drug plasma clearance as a proxy for CYP enzyme activity in patient populations. The tool developed in this study can support researchers in determining alterations in CYP enzyme activity in patients with (patho)physiological conditions.

Lefamulin dosing optimization using population pharmacokinetic and pharmacokinetic/pharmacodynamic assessment in Chinese patients with community-acquired bacterial pneumonia.

Lefamulin is the first pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). However, the pharmacokinetic/pharmacodynamic (PK/PD) characteristics in Chinese CABP patients are not fully understood. This study aimed to evaluate its microbiological efficacy against Streptococcus pneumoniae and Staphylococcus aureus via PK/PD analysis. The population PK (PopPK) model, established with foreign data was validated using data from Chinese CABP patients. PK/PD analysis was conducted for the intravenous administration of 150mg q12h for 1-h, 1.5-h and extended 2-h infusion. Oral administrations of 600mg q12h were assessed, considering original and higher plasma protein binding. Lefamulin displayed similar PK characteristics in both Chinese and Western populations. The PopPK model effectively predicted lefamulin concentrations in Chinese CABP patients. Under the dosage regimen of 150mg q12h via intravenous infusion for 1/1.5/2h, the probability of target attainments reached 98% at the minimum inhibitory concentration for both 90% S. pneumoniae and S. aureus, considering both original and higher protein binding rates. It is advisable to extend the infusion duration from 1/1.5 h-2h to minimize the risk of adverse effects at the infusion site. Regardless of fasted or fed conditions, the PTAs for 600mg q12h lefamulin via oral administration proved comparable to those for intravenous administration. This study proved that intravenous and oral administrations of lefamulin can reach preclinical PK/PD targets of S. pneumoniae and S. aureus. These findings support the optimal use of lefamulin for the safe and effective treatment of Chinese CABP patients.

Simultaneous determination of the combined and free concentrations of atorvastatin and its major metabolite in vitro and in vivo based on ultrafiltration coupled with UPLC-MS/MS method: an application in a protein binding rate and metabolism ability study in uremic hemodialysis patients

IntroductionA rapid, accurate, and specific ultrafiltration with ultra-performance liquid chromatographic-tandem mass spectrometry method was validated for the simultaneous determination of the protein binding rate of atorvastatin in uremic patients. Methods: The plasma samples were centrifuged at 6,000 r/min for 15 min at 37°C and the ultrafiltrate was collected. An ACQUITY UPLC® BEH C18 Column with gradient elution of water (0.1% formic acid) and acetonitrile was used for separation at a flow rate of 0.4 ml/min.ResultsThe calibration curves of two analytes in the serum showed excellent linearity over the concentration ranges of 0.05-20.00 ng/ml for atorvastatin, and 0.05-20.00 ng/ml for orthohydroxy atorvastatin, respectively. This method was validated according to standard US food and drug administration and European medicines agency guidelines in terms of selectivity, linearity, detection limits, matrix effects, accuracy, precision, recovery, and stability. This assay can be easily implemented in clinical practice to determine the free and combined concentrations of atorvastatin in the plasma of uremic patients. The final result showed that the average plasma protein binding rate in uremic patients was 86.58 ± 2.04%, relative standard deviation (RSD) (%) = 1.98, while the plasma protein binding rate in patients with normal renal function was 97.62 ± 1.96%, RSD (%) = 2.04. There was a significant difference in the protein binding rate in different types of plasma (P &amp;lt; 0.05), and the protein binding rate decreased with increasing creatinine until it stabilized at nearly 80%. The mean metabolite/prototype ratio of atorvastatin in patients with normal renal function and in patients with uremia was 1.085 and 0.974, respectively.DiscussionThe metabolic process of atorvastatin may be inhibited in uremic hemodialysis patients, but the total concentration of atorvastatin did not change significantly; due to the decrease of protein binding rate increase the drug distribution of atorvastatin in the liver or muscle tissue, which may increase the risk of certain adverse reactions. We recommend that clinicians use free drug concentration monitoring to adjust the dose of atorvastatin to ensure patient safety for uremic hemodialysis patients.

Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations: insights from a pharmacometric simulation study.

The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear. Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest. Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis. Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination. This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.

Plasma protein binding of arsenic species in acute promyelocytic leukemia patients and their relationships with hepatic and renal function

ABSTRACT Objectives Percentage protein binding (%PB) of arsenic species in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide remains unclear. It can be different depending on the status of hepatic or renal function. Methods This study obtained steady-state blood samples from normal APL patients and those with hepatic or renal impairment. %PB of inorganic arsenic (iAs), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) was determined by analyzing free and total plasma concentrations using ultrafiltration method by HPLC-HG-AFS. Results There is a linear relationship between free and total plasma concentrations for iAs (r2 = 0.952), MMAV (r2 = 0.603), and DMAV (r2 = 0.945). For patients with normal hepatic and renal function, mean %PB was as follows: iAs at 26.7 ± 14.3%, MMAV at 53.3 ± 11.9%, and DMAV at 24.7 ± 7.8%. %PB decreased in patients with renal impairment, with MMAV and DMAV showing statistically significant differences (p < 0.05 for MMAV, p < 0.01 for DMAV). No significant differences in %PB between normal and hepatic impairment group were observed. Conclusion Free arsenic species fraction can be estimated by total concentration. DMAV and iAs present low %PB, while MMAV exhibits a relatively high %PB in plasma. Level of %PB is more likely to be affected by renal function and age.

Larvicidal activity, molecular docking, and molecular dynamics studies of 7-(trifluoromethyl)indolizine derivatives against Anopheles arabiensis.

A novel series of 7-(trifluoromethyl)indolizine derivatives (4a-4n) was synthesized using a 1,3-Dipolar cycloaddition reaction. Structure elucidation of the synthesized compounds was done using various spectroscopic techniques. Compounds were assessed for their larvicidal activity against Anopheles arabiensis. Exposure of Anopheles arabiensis larvae to a series of 7-(trifluoromethyl)indolizine at 4µg/mL for 24 and 48h resulted in moderate to high larval mortality rates. Among them, compounds 4b, 4a, 4g, and 4m exhibited the most promising larvicidal activities, with mortality rates of 94.4%, 93.3%, 80.00%, and 85.6%, respectively, compared to controls, Acetone and Temephos. The structural activity relationship analysis of the evaluated compounds revealed that substitution with halogens or electron-withdrawing groups (CN, F, Cl, Br) at the para position of the benzoyl group is crucial for achieving promising larvicidal activity. Molecular docking studies were carried out involving six potential larvicidal target proteins to predict how the tested compounds might work. Compounds 4a and 4b showed strong binding to the Mosquito Juvenile Hormone-Binding Protein (5V13). Molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complexes over the simulation period, reinforcing the reliability of the docking results. Compounds 4a and 4b also exhibited favourable ADMET profiles, showing high oral bioavailability, good permeability, moderate distribution, low plasma protein binding, sufficient metabolic stability, efficient renal clearance and low toxicity. Given the crucial role of Juvenile Hormone in regulating gene expression and developmental pathways through receptor interactions, compounds 4a and 4b show promise as inhibitors of this protein. Inhibiting this process could hinder larval growth and reproduction, presenting a promising approach for early-stage mosquito larvicidal activity. Therefore, compounds 4a and 4b represent lead candidates for further optimization and the development of new larvicidal agents.

Target-site cefiderocol pharmacokinetics in soft tissues of healthy volunteers.

Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs. In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h_free_tissue/AUC0-8h_free_plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations. Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics. This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues.

Intercalating compounds alongside DNA helicase Q1 Plasmodium falciparum 3D7: Assessments of the Pharmacokinetic Properties Prediction of ADME.

Quantum chemical & molecular docking practices to deliver new perceptions into how etoposide, novobiocin, nogalamycin and netropsin interact with the biological targets PF3D7_0918600 (Plasmodium falciparum 3D7). Further the pharmacokinetics of a drug candidate which influenced by a variety of factors, including P- glycoprotein (Pgp) transport, PBB (Plasma protein binding), & BBB (Blood-brain barrier) permeation help to forecast the pharmacological characteristics of acetyl-CoA reductase inhibitors (ADMEs) and their metabolites. At this point, we have elevated four compounds such as etoposide, novobiocin, nogalamycin & netropsin. We have also studied molecular docking against the target protein of the Plasmodium falciparum (PF3D7_0918600) through exhausting the AutoDock Vina platform and AutoDock-Tools (ADT) and pharmacokinetic properties were carried out using the ADMET 2.0. The relative results of molecular docking recommended a greater binding affinity of novobiocin with the selected receptors among other compounds. In-silico ADME screening is a computational approach utilised to forecast the pharmacological characteristics of acetyl- CoA reductase inhibitors (ADMEs) and their metabolites. The ADMEs are based on the adsorption-desorption kinetics and pharmacopoeia. Adsorption and distribution analysis are used to assess the potential of the drug candidate. In vitro ADME is exploited to expect the effect of Pgp transport on the drug candidates. ADME has been used to predict CYP1A2 inhibitors and to predict PPB and BBB penetration. This paper summarizes the current knowledge on molecular docking, ADME and identifies potential drug candidates for ADME in vitro and in vivo.

Docking, Synthesis, and In vitro Anti-depressant Activity of Certain Isatin Derivatives.

In vitro, the molecular docking method has been suggested for estimating the biological affinity of the pharmacophores with physiologically active compounds. It is the latter stage in molecular docking, and the docking scores are examined using the AutoDock 4.2 tool program. The chosen compounds can be evaluated for in vitro activity based on the binding scores, and the IC50 values can be computed. The purpose of this work was to create methyl isatin compounds as potential antidepressants, compute physicochemical characteristics, and carry out docking analysis. The protein data bank of the RCSB (Research Collaboratory for Structural Bioinformatics) was used to download the PDB structures of monoamine oxidase (PDB ID: 2BXR) and indoleamine 2,3-dioxygenase (PDB ID: 6E35). Based on the literature, methyl isatin derivatives were chosen as the lead chemicals. By determining their IC50 values, the chosen compounds were tested for in vitro anti-depressant activity. The binding scores for the interactions of SDI 1 and SD 2 with indoleamine 2,3 dioxygenase were found to be -10.55 kcal/mol and -11.08 kcal/mol, respectively, while the scores for their interactions with monoamine oxidase were found to be -8.76 kcal/mol and -9.28 kcal/mol, respectively, using AutoDock 4.2. The relationship between biological affinity and pharmacophore electrical structure was examined using the docking technique. The chosen compounds were tested for their ability to inhibit MAO, and the IC50 values for each were found to be 51.20 and 56, respectively. This investigation has identified many novel and effective MAO-A inhibitors from the family of chemicals known as methyl isatin derivatives. Lead optimization was applied to the SDI 1 and SDI 2 derivatives. The superior bioactivity, pharmacokinetic profile, BBB penetration, pre-ADMET profiles, such as HIA (human intestinal absorption) and MDCK (Madin-Darby canine kidney), plasma protein binding, toxicity assessment, and docking outcomes, have been obtained. According to the study, synthesised isatin 1 and SDI 2 derivatives exhibited a stronger MAO inhibitory activity and effective binding energy, which may help prevent stress-induced depression and other neurodegenerative disorders caused by a monoamine imbalance.

Synthesis and structure-affinity relationships of spirocyclic σ1 receptor ligands with tetrahydropyran scaffold

The σ1 receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ1 receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ1 receptor affinity and selectivity over related targets. The σ1 affinity of the ligands was correlated with their lipophilicity (logD7.4 value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative 5i showed a promising balance of high σ1 affinity (Ki(σ1) = 3.9 nM) and selectivity (> 250-fold) as well as high LLE of 5.8. 5i has a high plasma protein binding (89%) and promising metabolic stability in the presence of mouse liver microsomes and NADPH (83% intact after 90 min). Increasing the size of the piperidine ring of the spirocyclic ligands 5 to an azepane ring led to considerably increased σ1 affinity (Ki(5a) = 1.2 nM, Ki(23a) = 0.42 nM) and selectivity over σ2 receptors (5a: 45-fold, 23a: 150-fold).

Chronopharmacokinetics: A Brief Analysis of the Influence of Circadian Rhythm on the Absorption, Distribution, Metabolism, and Elimination of Drugs

Chronopharmacokinetics is a specialized field within pharmacokinetics that focuses on how the timing of drug administration affects the absorption, distribution, metabolism, and elimination of drugs. The circadian rhythm, governed by the body's biological clock, plays a crucial role in pharmacokinetics, which encompasses the absorption, distribution, metabolism, and elimination of drugs. These pharmacokinetic processes are subject to daily variations influenced by the circadian rhythm. Drug absorption can fluctuate due to changes in gastrointestinal function, such as motility and gastric pH, and blood circulation. Similarly, the distribution of drugs in the body is influenced by factors such as tissue perfusion, plasma protein binding, and cell membrane permeability, all of which are modulated by the circadian rhythm. Metabolism, especially hepatic metabolism, can also experience circadian variations that affect the rate at which drugs are processed and converted into active or inactive metabolites. Finally, the elimination of drugs, primarily through renal function, can show circadian rhythms that impact the excretion of compounds from the body. Understanding these circadian fluctuations is essential to optimize the efficacy and safety of pharmacological treatments, as dosages and administration times could be adjusted to align with the peaks of biological clock activity. Thus, treatments can be more effective and have fewer side effects by leveraging the circadian variability in pharmacokinetic processes.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Pritelivir and Its Metabolites.

Two trials were performed to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of pritelivir and its metabolites. The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects. Following a single oral dose of 100mg of pritelivir, mild and moderate renal impairment and moderate hepatic impairment did not have a clinically relevant effect on the pharmacokinetics of pritelivir. In subjects with severe renal impairment, pritelivir exposure (area under the plasma concentration-time curve from time 0 to infinity (AUC0- inf) was 57% higher compared with controls. Pritelivir plasma protein binding was similar in subjects and controls with renal impairment, while the free fraction was higher in subjects with moderate hepatic impairment, increasing unbound pritelivir exposure by 23%. For the metabolites pyridinyl phenyl acetic acid (PPA), amino thiazole sulfonamide (ATS), and PPA-acyl glucuronide, generally higher exposure was observed with increasing degree of renal impairment (ie, moderate to severe), but not with mild impairment. A modest effect of moderate hepatic impairment was observed for PPA and ATS. Pritelivir was safe and well tolerated in healthy subjects and subjects with renal or hepatic impairment.

Development and Validation of an LC-MS/MS Assay for the Quantitation of MO-OH-Nap Tropolone in Mouse Plasma: Application to In Vitro and In Vivo Pharmacokinetic Studies.

A rapid, selective, and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of MO-OH-Nap tropolone (MO-OH-Nap) in mouse plasma. MO-OH-Nap is an α-substituted tropolone with anti-proliferative properties in various cancer cell lines. Detection and separation of analytes was achieved on an ACE Excel C18 (1.7 µm, 100 × 2.1 mm, MAC-MOD Analytical, Chadds Ford, PA, USA) column with mobile phase consisting of 0.05% trifluoroacetic acid in water (mobile phase A) and 0.05% trifluoroacetic acid in acetonitrile (mobile phase B), with an isocratic elution of 15:85% (A:B) at a total flow rate of 0.25 mL/min. The LC-MS/MS system was operated at unit resolution in multiple reaction monitoring (MRM) mode, using precursor ion > product ion combination of 249.10 > 202.15 m/z for MO-OH-Nap and 305.10 > 215.05 m/z for the internal standard (IS), BA-SM-OM. The MS/MS response was linear over a concentration range of 1 to 500 ng/mL with a correlation coefficient (r2) of ≥0.987. The within- and between-batch precision (%RSD) and accuracy (%Bias) were within acceptable limits. The validated method was successfully applied to determine MO-OH-Nap metabolic stability, plasma protein binding, and bio-distribution studies of MO-OH-Nap in CD-1 mice.