Study of Pharmacokinetics for Ivermectin B1a from Beagle Dogs.

Ivermectin has been widely used for antiparasitic drug, and has recently shown a broad-spectrum antiviral activity, including anti-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the pharmacokinetic property of ivermectin has not been fully investigated yet. During the plasma preparation, ~32-46% of ivermectin was found in the precipitation.

Influence of two-period cross-over design on the bioequivalence study of gefitinib tablets in beagle dogs.

Generally, two-period cross-over design is used in bioequivalence (BE) study. High intra-subject variability of gefitinib was reported in a clinical BE study, and significant changes in gefitinib exposures were observed among different periods in our previous BE study in dogs. Therefore, commercial gefitinib tablets from the same batch were used in the present study and assigned to two groups: the testing drug (GF1) group and the reference drug (GF2) group.

Inhibition effects of eight anti-coronavirus drugs on glycosides metabolism and glycosidases in human gut microflora.

The effects of eight oral anti-coronavirus drugs (lopinavir, ritonavir, chloroquine, darunavir, ribavirin, arbidol, favipiravir, oseltamivir) on the metabolism of four specific glycosides (polydatin, geniposide, quercitrin, glycyrrhizin) and on the activities of three major glycosidases (β-glucosidase, α-rhamnosidase, β-glucuronidase) from gut microflora were explored and determined by LC-MS/MS. The metabolism of polydatin, geniposide, quercitrin and glycyrrhizin was significantly inhibited by one or several anti-coronavirus drugs of 100 μM around 1 h and 4 h (P<0.05), among which darunavir could strongly reduce the production of genipin (70.

Roles of diclofenac and its metabolites in immune activation associated with acute hepatotoxicity in TgCYP3A4/hPXR-humanized mice.

Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug, but it comes with a high risk of drug-induced liver injury (DILI). Despite the quinone-imine adduct pathways, the immunotoxicity is recently considered as another factor for DILI. However, such immune responses are still elusive.

Studies on oral bioavailability and first-pass metabolism of withaferin A in rats using LC-MS/MS and Q-TRAP.

Withaferin A (WA) is one of the major bioactive steroidal lactones with extensive pharmacological activities present in the plant Withania somnifera. The absolute oral bioavailability of WA remains unknown and human-related in vitro data are not available. Therefore, in the present study, the absolute oral bioavailability of WA in male rats and the in vitro screening of absorption factors by Q-trap and LC-MS/MS analysis were conducted to explore possible clinical properties of WA.

Studies of pharmacokinetics in beagle dogs and drug-drug interaction potential of a novel selective ZAK inhibitor 3h for hypertrophic cardiomyopathy treatment.

Overexpression of leucine-zipper and sterile-α motif kinase (ZAK) in heart has been closely associated with the development of hypertrophic cardiomyopathy (HCM). N-(3-(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl) benzene-sulfonamides, novel highly selective ZAK inhibitors, had exhibited reasonable orally therapeutic effects on HCM in spontaneous hypertensive rat models. In the present study, a rapid and sensitive HPLC-MS/MS method for determining ZAK inhibitor 3h in beagle dog plasma was developed and validated.

Improved defined approaches for predicting skin sensitization hazard and potency in humans.

Since the EU banned animal testing for cosmetic products and ingredients in 2013, many defined approaches (DA) for skin sensitization assessment have been developed. Machine learning models were shown to be effective in DAs, but the predictivity might be affected by data imbalance (i.e.

Comparison of in vitro/in vivo blood distribution and pharmacokinetics of artemisinin, artemether and dihydroartemisinin in rats.

Artemisinin and its derivatives have been widely used for treatment of malaria and the therapeutic targets are considered within the red blood cells. In the recent studies on the erythrocytes' uptake of artemisinin-derivatives in vitro, applying the radioisotope-labeled technology, it was trying to predict the in vivo disposition properties, but different distribution results were revealed from a preliminary study in one human. The pharmacokinetic differences among blood cells and plasma still remain unclear.

Development of an optimized cytotoxicity assay system for CYP3A4-mediated metabolic activation via modified piggyBac transposition.

Drug-induced hepatotoxicity is often caused by cytochrome P450 (CYP)-dependent metabolism of drugs into reactive metabolites. Assessment of hepatotoxicity induced by bioactive compounds is hampered by low CYP expression within in vitro cell lines. To overcome this limitation, piggyBac transposition and monoclonal expansion were used to generate a HepG2 cell line with stable and homogenously high expression of CYP3A4, a prominent CYP isoform.

Determination of a novel dipeptidyl peptidase IV inhibitor in monkey plasma by HPLC-MS/MS and its application in a pharmacokinetics study.

A lot of attention has been given to novel diabetes treatment, which is used to replace injectable insulin. A novel dipeptidyl peptidase IV inhibitor (HWH-10d) for treating type 2 diabetes was previously determined to have comparable efficacy to the marketed drug (alogliptin) in ICR male mice. Therefore, a sensitive and rapid liquid chromatography-tandem mass spectrometric method was developed and validated for the further evaluation of HWH-10d in monkey.

Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs.

Ethnopharmacological Relevance: Hypaconitine is one of the main aconitum alkaloids in traditional Chinese medicines prepared with herbs from the genus Acotinum. These herbs are widely used for the treatment of cardiac insufficiency and arrhythmias. However, Acotinum alkaloids are known for their toxicity as well as their pharmacological activity, especially cardiotoxicity including QT prolongation, and the mechanism of this toxicity is not clear.

Different binding sites of bovine organic anion-transporting polypeptide1a2 are involved in the transport of different fluoroquinolones.

Because of their wide distribution and capability of transporting a large variety of compounds, organic anion-transporting polypeptides (OATPs) have been extensively recognized as crucial players in absorption, distribution, and excretion of various drugs. OATP1A2 was the first cloned human OATP and has been found to transport wide range of endogenous and exogenous compounds. Bovine Oatp1a2 (bOatp1a2) shares high homology with human OATP1A2 and is considered the functional ortholog of the latter.

Metabolism of fenofibrate in beagle dogs: new metabolites identified and metabolic pathways revealed.

Fenofibrate is a prototypical agonist of peroxisome proliferator-activated receptor alpha (PPARalpha) which is well known to be associated with species related carcinogenesis. Important species differences have been reported in its metabolism and elimination pattern. Its new metabolites have been revealed in Cynomolgus monkeys and Sprague-Dawley rats.

Validation of visualized transgenic zebrafish as a high throughput model to assay bradycardia related cardio toxicity risk candidates.

Drug-induced QT prolongation usually leads to torsade de pointes (TdP), thus for drugs in the early phase of development this risk should be evaluated. In the present study, we demonstrated a visualized transgenic zebrafish as an in vivo high-throughput model to assay the risk of drug-induced QT prolongation. Zebrafish larvae 48 h post-fertilization expressing green fluorescent protein in myocardium were incubated with compounds reported to induce QT prolongation or block the human ether-a-go-go-related gene (hERG) K⁺ current.

Relaxation of rat thoracic aorta by fibrate drugs correlates with their potency to disturb intracellular calcium of VSMCs.

Phenotypic modifications of vascular smooth muscle cells (VSMCs) contribute to pathological changes in atherosclerosis where modulation of intracellular calcium plays an important role. In this study, three fibrate drugs, namely gemfibrozil (Gem), fenofibric acid (Fa) and bezafibrate (Beza), were revealed to relax thoracic aorta associated with their potency to reduce intracellular calcium ([Ca²⁺]i) in cultured VSMCs. Relaxation effect of Gem, Fa and Beza was assayed on precontracted rat aortic rings.

Drug-drug interactions between ketoconazole and berberine in rats: pharmacokinetic effects benefit pharmacodynamic synergism.

Ketoconazole (KTZ), a clinical antifungal agent, is a known inhibitor of CYP3A and permeability glycoprotein (P-gp). Berberine (BBR), a natural plant-derived product used for gastroenteritis, is a substrate of P-gp. Recently, a synergistic antifungal effect of KTZ combined with BBR has been revealed.

Induction of P450 3A1/2 and 2C6 by gemfibrozil in Sprague-Dawley rats.

Fibrates are a group of peroxisome proliferator-activated receptor α agonists used in the treatment of dyslipidemia; however, they have been reported to cause species-related hepatocarcinogenesis and clinical myotoxicity. Gemfibrozil is one of the most commonly used fibrates, and it shows the highest risk for myotoxicity among the fibrates. The inhibitory drug-drug interaction mechanism associated with gemfibrozil has been explored recently, and the induction of human P450 3A4 and 2C8 has been reported.

Biphasic regulation of intracellular calcium by gemfibrozil contributes to inhibiting L6 myoblast differentiation: implications for clinical myotoxicity.

Gemfibrozil is the most myotoxic fibrate drug commonly used for dyslipidemia, but the mechanism is poorly understood. The current study revealed that gemfibrozil inhibits myoblast differentiation through the regulation of intracellular calcium ([Ca(2+)]i) as revealed in L6 myoblasts by use of laser scan confocal microscopy and flow cytometry using Fluo-4 AM as a probe. Gemfibrozil at 20-400 μM, could regulate [Ca(2+)]i in L6 cells in a biphasic manner, and sustained reduction was observed when the concentration reached 200 μM.

The highly potent and selective dipeptidyl peptidase IV inhibitors bearing a thienopyrimidine scaffold effectively treat type 2 diabetes.

New dipeptidyl peptidase IV inhibitors were designed based on Alogliptin using a scaffold-hopping strategy. All of the compounds constructed on a thienopyrimidine scaffold demonstrated good inhibition and selectivity for DPP-IV. Compound 10d exhibited subnanomolar (IC(50)=0.

The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors.

Human uridine-5'-diphosphoglucuronosyltransferases (UGTs) are the major phase II metabolizing enzymes. In the present study, five human UGTs (UGT1A1, 1A4, 1A6, 2B7, and 2B10) were individually expressed and used to examine the inhibition IC(50) values of 20 selective substrates and inhibitors of major cytochromes P450 (CYPs). The inhibition kinetics of UGT1A1 was also analyzed.

Simultaneous analysis of bambuterol and its active metabolite terbutaline enantiomers in rat plasma by chiral liquid chromatography-tandem mass spectrometry.

A chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) simultaneous stereoselective analysis of bambuterol and its active metabolite terbutaline enantiomers in Wistar rat plasma has been developed and validated. All analytes and the internal standard were extracted from rat plasma samples by liquid-liquid extraction, separated on macrocyclic glycopeptide teicoplanin column with mobile phase constituted of 20mM ammonium acetate solution-methanol (10:90, v/v) at a flow-rate of 0.4 mL/min.

Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics.

Fenofibrate, widely used for the treatment of dyslipidemia, activates the nuclear receptor, peroxisome proliferator-activated receptor alpha. However, liver toxicity, including liver cancer, occurs in rodents treated with fibrate drugs. Marked species differences occur in response to fibrate drugs, especially between rodents and humans, the latter of which are resistant to fibrate-induced cancer.

Myotoxicity of gemfibrozil in cynomolgus monkey model and its relationship to pharmacokinetic properties.

Fibrate drugs are PPARalpha agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo.

An inhibition study of beauvericin on human and rat cytochrome P450 enzymes and its pharmacokinetics in rats.

Beauvericin is a secondary metabolite natural product from microorganisms and has been shown to have a new potential antifungal activity. In this study, the metabolism and inhibition of beauvericin in human liver microsomes (HLM) and rat liver microsomes (RLM) were investigated. The apparent K(m) and V(max) of beauvericin in HLM were determined by substrate depletion approach and its inhibitory effects on cytochromes P450 (CYP) activities were evaluated using probe substrates, with IC(50) and the (K(i)) values were 1.