Abstract Nafithromycin is a next generation lactone ketolide antibiotic slated to enter phase III clinical development in India for the treatment of CABP as a shorter 800mg-OD X3 day therapeutic regimen. Nafithromycin exhibits potent activity against MDR Streptococcus pneumoniae including erythromycin and telithromycin-resistant resistant strains. Older macrolides/ketolides are reported to be potent

Abstract Dilated cardiomyopathy (DCM) is a disease of the myocardium defined by left ventricular enlargement and systolic dysfunction leading to heart failure. Danicamtiv, a new targeted myosin activator designed for the treatment of DCM, was characterized in in vitro and in vivo preclinical studies. Danicamtiv human hepatic clearance was predicted to be 0.5 mL/min/kg from in vitro metabolic stability

Abstract 2´-Hydroxyflavanone (2´OHFva), 3´OHFva, 4´OHFva, and 6OHFva, the major oxidative products of flavanone by human cytochrome P450 (P450, CYP) enzymes, were studied in regard to further oxidation by human CYP1A1, 1A2, 1B1.1, 1B1.3, and 2A6. The products formed were analyzed with LC-MS/MS and characterized by their positive ion fragmentations on mass spectrometry. Several di-hydroxylated flavanone

Abstract We investigated the plasma toxicokinetic behavior of free (parent) and total (parent and conjugated forms) of bisphenol S (BPS) and bisphenol AF (BPAF) in plasma of adult male rats and mice following exposure via feed for 7 d to BPS (338, 1125, and 3375 ppm) or BPAF (338, 1125, and 3750 ppm). In rats, the exposure concentration-normalized maximum concentration (Cmax/D (ng/mL)/(ppm)) and area

(2020). Correction. Xenobiotica. Ahead of Print.

During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic models

1. Scutellarin is a flavonoid glycoside widely used in the treatment of cardio-cerebrovascular diseases in China. In this study, we investigated the effect of scutellarin on cytochrome P450 3A4 (CYP3A4) and CYP3A5 expression. Furthermore, we studied the expression of hsa-miR-27a, hsa-miR-27b, hsa-miR-148a, hsa-miR-298 and hsa-miR-451a in humans to determine whether scutellarin regulated CYP3A4 and

Time-dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis of microsomal assays. Additionally, a distinct terminal inactivation step was identified for certain mechanism based inhibitors (MBI) following reversible metabolite intermediate complex (MIC) formation. Longer hepatocyte incubations

Hesperidin (HPD) and hesperetin (HPT), as a kind of flavonone compounds, are abundant in citrus fruits with various pharmacological effects. HPD and HPT are not always consistent in some biological activities, even if they have the same skeletal structure. The aim of this study was to screen and identify HPT and HPD metabolites in rats using UHPLC-LTQ-Orbitrap MS n , compare the possible metabolism

Genistein is a widely studied phytoestrogen. The effects of genistein on myoblasts were reported long ago, but the conclusions are controversial. In this study, we evaluated the effects of different concentrations of genistein on C2C12 myoblasts. Genistein treatment promoted myoblast proliferation in a dose-dependent manner in the concentration range of 0–2 µM/L, reaching its maximum effect at 2 µM/L

Lumefantrine (LFN) is a chiral anti-malarial drug. Enantioselective in vitro attributes and absolute oral pharmacokinetics for (-)-LFN and (+)-LFN have been characterized in mice. No stereoselectivity was seen with either of the enantiomers when compared with rac-LFN in the executed in vitro studies (solubility, metabolic stability, protein binding, permeability and blood partitioning). Post intravenous

Dronedarone and ticagrelor have high co-administration potential in patients with both acute coronary syndrome and atrial fibrillation. The objective of the present in-vivo study was to investigate the potential interaction between dronedarone (5 and 10 mg/kg) and ticagrelor (5 and 10 mg/kg) when administered orally to rats. Forty Sprague-Dawley rats were randomly distributed into eight groups; consisting

Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with juvenile dermatomyositis (JDM) and optimize the limited sampling strategy (LSS)

This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of 3H-erdafitinib and 14C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), 3H-erdafitinib to intact dogs (0.25 mg/kg), and 14C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (Tmax: animals, 1 hour; humans,

Fluorofenidone(AKF-PD) is an analog of pirfenidone and shows stronger antifibritic effect and lower toxicity compared to pirfenidone in preclinical studies. However, the inhibitory and inducible effects of AKF-PD on human CYP450s are unclear. The aim of this study was to evaluate the ability of AKF-PD to inhibit and induce CYP450s in vitro. In inhibition study, the inhibitory effects of CYP1A2, CYP3A4

The formation of reactive metabolites is a problem in drug development that sometimes results in severe hepatotoxicity. Because detecting reactive metabolites themselves is difficult, a covalent binding assay using expensive radiolabelled tracers is usually performed for candidate selection. This study aimed to provide a practical approach toward the risk assessment of hepatotoxicity induced by covalent

Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined. Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days)

Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-β-D glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporters is still fragmented. The aim of the present study was to explore these interactions with

UR-1102, a novel urisocuric agent for treating gout, has been confirmed to exhibit a pharmacological effect in patients. We clarified its metabolic pathway, estimated the contribution of each metabolic enzyme, and assessed the impact of genetic polymorphisms using human in vitro materials. Glucuronide, sulfate, and oxidative metabolites of UR-1102 were detected in human hepatocytes. The intrinsic clearance

1. In the cynomolgus macaque, UDP-glucuronosyltransferases (UGTs) 1As have similar molecular and enzymatic characteristics to those of their human orthologs. However, genetic polymorphisms in major cynomolgus UGT1A1/6/9 have not been investigated. 2. We re-sequenced UGT1A1, UGT1A6, and UGT1A9 in 186 cynomolgus macaques (bred in Cambodia, China, or Indonesia) and 54 rhesus macaques and found 15, 13

The use of IBH-5 decreased the kdeg values and increased the half-life of the compounds PNZ, TCP, Cpd I and Cpd II with kdeg values of 1.10 × 10−4 s− 1 (t1/2 = 115 min), 4 × 10−5 s−1 (t1/2 = 289 min), 4 × 10−5 s−1 (t1/2 = 289 min), and 3 × 10−5  s−1 (t1/2 = 385 min) respectively, compared to kdeg values of 1.25 × 10−2  s−1 (t1/2 = 0.9 min), 1.1 × 10−4 s−1 (t1/2 = 105 min), 1.0 × 10−3 s−1 (t1/2 = 11

We investigated the influence of multiple oral administration on the accumulation of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, in rats. It is well known that orally administered dalcetrapib is rapidly hydrolysed to its active form, which has a sulfhydryl group, in the body. The active form then binds covalently to endogenous thiols via mixed disulfide bonds

The unbound fractions in plasma (fup) in two mouse models of humanized liver mice, PXB and humanized TK-NOG mice, were compared with human fup values using equilibrium dialysis method. A good relationship between fup values obtained from PXB mice and humans was observed; the fup of 34/39 compounds (87.2%) in PXB mice were within 3-fold of human fup. In contrast, a weak correlation was observed between

The kinetics of metabolism of deltamethrin (DLM) and cis- and trans-permethrin (CPM and TPM) was studied in male Sprague-Dawley rat and human liver microsomes. DLM metabolism kinetics was also studied in isolated rat hepatocytes, liver microsomes and cytosol. Apparent intrinsic clearance (CLint) values for the metabolism of DLM, CPM and TPM by cytochrome P450 (CYP) and carboxylesterase (CES) enzymes

Targeted covalent inhibitors designed to bind covalently to a specific molecular target have recently been a focus of drug development. Among these inhibitors, thiol compounds bind covalently to endogenous thiols in the body through a process involving disulfide bonds. We investigated the predictability of changes in the exposure to captopril, tiopronin, the active form of dalcetrapib and the active

Knowledge of inter-strain and inter-gender differences in drug metabolism studies is important for animal selection in pharmacokinetic and toxicological studies. The effects of rat strain and gender in in vitro metabolism were investigated in Sprague Dawley (SD) and Wister Han (WH) rats based on the hepatocyte metabolic profiles of 14 small molecule drugs. Similarities were found between the hepatocyte

Partial or complete deficiency in the dihydropyrimidine dehydrogenase (DPD) has been observed in 3%–5% and 0.1% of the general population, respectively. It causes severe toxicity in the context of 5-fluorouracil (5-FU) therapy. However, the current tests for determination of DPD deficiency have limitations in routine clinical usage. Therefore, an in vitro approach for simulating 5-FU degradation was

The metabolism of bifenthrin (BIF), β-cyfluthrin (CYFL), λ-cyhalothrin (CYHA), cyphenothrin (CYPH) and esfenvalerate (ESF) was studied in liver microsomes, liver cytosol and plasma from male Sprague-Dawley rats aged 90, 21 and 15 days and from adult humans. Pyrethroid metabolism was also studied with some human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. All five pyrethroids

We closely characterized 7-Dimethylamino-4-trifluromethylcoumarin (Coumarin 152, C152), a substrate metabolized by multiple P450 species, to establish a new fluorogenic probe for the studies of functional integration in the cytochrome P450 ensemble, Scanning fluorescence spectroscopy and LC/MS-MS were used to characterize the products of N-demethylation of C152 and optimize their fluorometric detection

MGV354 was being developed as a novel ocular therapy for lowering of intraocular pressure, a key modifiable risk factor for glaucoma. MGV354 is an activator of soluble guanylate cyclase, an enzyme known to be involved in the regulation of IOP. MGV354 has been shown to robustly lower IOP over 24 hours after a single topical ocular drop in rabbit and monkey pharmacology models. However, MGV354 failed

Fenarimol (FNL), an organic chlorinated fungicide, is widely used in agriculture for protection from fungal spores and fungi. Despite being an endocrine disruptor, no toxicokinetic data is reported for this fungicide. In the present work, we determined the plasma protein binding, metabolic pathways and toxicokinetics of FNL in rats. In vitro binding of FNL to rat and human plasma proteins was ∼90%

Hydrocoptisonine is a new compound that has been isolated from the rhizomes of Coptis chinensis, which belongs to the Ranunculaceae family of Chinese medicines. Although studies on C. chinensis have been reported, the metabolic pathway of hydrocoptisonine in human liver microsomes (HLMs) remains unelucidated. We identified 13 metabolites in HLMs, including six Phase I metabolites and seven glucuronide

Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9, and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously

The study aims to establish the plasma pharmacokinetic parameters of levofloxacin in mixed-breed dogs, at a single dose of 5 mg/kg, intravenously, orally only and orally with sucralfate pre-treatment (1g per animal), to evaluate its influence on antimicrobial absorption. Concentrations of levofloxacin in plasma were determined using high performance liquid chromatography (HPLC) with fluorescence detection

Quercetin (QCN) is commonly used in high doses as dietary supplement for weight loss. Psychotic patients are at greater risk of developing obesity than the general population. The present study was designed to understand the impact of QCN on the exposure of quetiapine (QTE), an anti-psychotic drug with narrow therapeutic index and brain penetrating capability. The content of QTE in rat plasma was analyzed

Although CYP2C19 is minor human liver enzyme, it is responsible for the metabolism of many clinically important drugs. In the present work, CYP2C19 wild type and its SNP mutants (R132Q and W120R) were prepared using over-expression system in E. coli, purified by column chromatography and their biological activities were compared. The enzyme activity toward certain drugs (amitriptyline, imipramine,

Challenges and opportunities within peptide ADME (absorption, distribution, metabolism and elimination) were presented and discussed at the 2nd workshop of the Peptide ADME Discussion Group in Cambridge, UK (17th of September 2019). This article summarises the presentations and discussions from this workshop. The following topics were covered: Peptide drug-drug interactions (DDIs) Regulatory perspectives

The specialty amine catalyst 2,2′-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female

Primates exhibit a high degree of among-species dietary diversity, which likely exposes them to varying levels of xenobiotic compounds. Here, we examined the evolution of primate CYP1-3 gene families, and we classified the 15 CYP1-3 gene subfamilies as either xenobiotic-metabolizing (XM) or endogenous-metabolizing (EM) based on sources in the P450 literature. We predicted that XM P450s would show (1)

To date, relatively little is known about the interactions of pharmaceutical excipients with hepatic and renal drug uptake transporters. The present study was designed to systematically evaluate the effects of sixteen commonly consumed excipients on human organic cation transporter 1 and 2 (hOCT1 and hOCT2), human organic anion transporter 1 and 3 (hOAT1 and hOAT3) and human organic anion transporting

TQ-A3326 has been developed as a new drug by modifying the structure of daclatasvir with deuterium. The pharmacokinetics (PK) of TQ-A3326 in human remains unclear. The aim of the present study was to establish a LC-MS/MS method to investigate preliminarily the PK characteristics of TQ-A3326 and its major metabolites in healthy Chinese volunteers. All volunteers were administrated TQ-A3326 (60 mg).

Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the in vitro drug–drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations. In vivo absorption-distribution-metabolism-excretion (ADME) studies

We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85-86%; urine, 3-6%) with no apparent dose-related effect. In male rats, 29% of the administered dose

Pesticides are now recognised to interact with drug transporters, but only few data are available on this issue for carbamate pesticides, a widely used class of agrochemicals, to which humans are highly exposed. The present study was therefore designed to determine whether four representative carbamate pesticides, i.e. the insecticides aminocarb and carbofuran, the herbicide chlorpropham and the fungicide

OATP1B1 is an important drug transporter with a complex regulatory mechanism. In this study, we wanted to investigate how LncRNA HOTAIR regulates the expression of OATP1B1 through its action on miR-206/miR-613 in HepG2 cells. The expression level of LncRNA HOTAIR, miR-206/miR-613, and OATP1B1 mRNA was detected by RT-qPCR, and the OATP1B1 protein level was detected by Western blot. The competitive endogenous

Diclofenac is an extensively used nonsteroidal anti-inflammatory drug, but gastrointestinal liabilities and cardiovascular complications take the shine away from such a widely prescribed drug. On the other hand, rutin, a dietary bioflavonoid, has quite a few pharmacological attributes to improve the efficacy and reduce the dose-related toxicities of diclofenac through the intended food-drug/herb-drug

We aimed to establish a population pharmacokinetic (PK) model of tacrolimus and identify clinical covariates, especially the genetic polymorphisms of CYP3A5, ABCB1 and POR*28 that affected the PK to prevent fluctuation in the trough concentration of tacrolimus during the early period after renal transplantation. Tacrolimus trough concentration, clinical data and CYP3A5/ABCB1/POR28 genotypes were retrospectively

The objective of this study was to compare the pharmacokinetics of vancomycin hydrochloride administered into rabbits through different routes and explore the feasibility of peptide drugs entering the systemic circulation through ocular administration. A convenient, accurate, and rapid liquid chromatography-trandem mass spectrometric (LC-MS/MS) method was established and used for the determination

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge

Recently, alternatives to animal testing have been used to evaluate skin sensitisers in cosmetic products. However, testing is still complicated and expensive. To develop a simpler, cost-effective and more accurate evaluation method for the skin sensitising chemicals, we employed cell-based and RT-PCR-based assay. Representative sensitiser specific gene expression in THP-1 cells was analysed by microarray

Horses are exposed to various kinds of medication, however, there are limited determinations of plasma clearance (CLp) for the drugs used due to the high cost of equine in vivo studies. Many of the CLp values generated come from the equine sports industry for determining drug plasma screening limits in the control of medications at the time of competition. The kinetics of omeprazole metabolism were

The compound 20(S),25-epoxydammarane-3β,12β,24α-triol (24-hydroxy-panaxadiol or 24-OH-PD), isolated from the red Panax ginseng CA Meyer possesses anticancer activity. Our aim was to study the pharmacokinetic characteristics of 24-OH-PD, which is essential for pre-clinical research during the development of new drugs. In this study, a simple and sensitive ultra-performance liquid chromatography-mass

We previously reported a prediction method for human pharmacokinetics (PK) using single species allometric scaling (SSS) and the complex Dedrick plot in chimeric mice with humanized liver to predict the total clearance (CLt), distribution volumes in steady state (Vdss) and plasma concentration-time profiles of several drugs metabolized by cytochrome P450 (P450) and non-P450 enzymes. In the present

Hepatocellular carcinoma (HCC) is a malignancy of liver cells. Recent studies have shown that HCC patients often have changes in the activities of transporters and metabolic enzymes, which can considerably affect drug pharmacokinetics and lead to drug toxicity. Doxorubicin (DOX) has been frequently administered in chemotherapy for HCC, but to our knowledge, the effects of HCC on the pharmacokinetics

Liver enzymes and transporters play an essential role in xenobiotic metabolism, distribution and elimination. Pre-clinical safety assessment relies on studies on animal models, including the (mini)pig. The pig shares many anatomical and physiological characteristics with humans, and there is currently a gap in information about porcine metabolism and disposition pathways and their similarities and

Ethanol, as a small-molecule organic compound exhibiting both hydrophilic and lipophilic properties, quickly pass through the biological barriers. Over 95% of absorbed ethanol undergoes biotransformation, the remaining amount is excreted unchanged, mainly with urine and exhaled air. The main route of ethyl alcohol metabolism is its oxidation to acetaldehyde, which is converted into acetic acid with

Peimine is a major component of Fritillaria ussuriensis, which is a widely used herb in pediatric. It is very common in Chinese traditional medicine to combine with two or more herbs in the clinic. To investigate the effect of peimine on the activity of cytochrome P450 enzymes (CYP450) is necessary for the clinical application of peimine. The effects of peimine on eight human liver CYP isoforms (i

Herbs are often administered in combination with therapeutic drugs, raising the possibility for herb–drug interactions (HDIs). Furoquinoline alkaloids are found in Rutaceae plants, which are structurally similar and have many medicinal properties. This study aims to investigate the inhibition of four furoquinoline alkaloids on the activity of UDP-glucuronosyltransferases (UGTs). The recombinant UGTs-catalyzed

2′-, 3′-, and 4′-Methoxyflavones (MeFs) were incubated with nine forms of recombinant human cytochrome P450 (P450 or CYP) enzymes in the presence of an NADPH-generating system and the products formed were analyzed with LC-MS/MS methods. CYP1B1.1 and 1B1.3 were highly active in demethylating 4′MeF to form 4′-hydroxyflavone (rate of 5.0 nmol/min/nmol P450) and further to 3′,4′-dihydroxyflavone (rates