Abstract: Acetaminophen is gaining importance as a first-line drug for treating patent ductus arteriosus (PDA) in neonates. Predominant metabolites of acetaminophen in preterm neonates vary from that of adults; and the drug is predominantly metabolized by conjugation and partly by Cytochrome P450 (CYP) enzymes. We carried out the present study to identify the principal urine metabolites of acetaminophen

Abstract 1. Morin, a natural flavonol, is present in many plants. It has anti-inflammatory and immunomodulatory activities and is often used as an adjuvant treatment for arthritis. Diclofenac sodium is the first-choice drug in the treatment of rheumatoid arthritis. However, the herb-drug interaction (HDI) between morin and diclofenac sodium remains unclear. 2. The aim of the present research was to

Abstract The disposition of a novel kynurenine monooxygenase inhibitor, CHDI-340246, was investigated in vitro and in animals. In vitro, there was minimal metabolic turnover of CHDI-340246 in all species. The protein binding was higher in human plasma (99.7%) relative to other species. In all species, blood clearance was low (<20% of liver blood flow) and volume of distribution was small (<0.5 L/kg)

Abstract Razuprotafib, a sulphamic acid-containing phosphatase inhibitor, is shown in vivo to undergo enzymatic oxidation and methylation to form a major metabolite in monkey and human excreta with an m/z– value of 633. LC-MS/MS analysis of samples derived from incubations of razuprotafib with human liver microsomes and recombinant CYP2C8 enzyme has elucidated the metabolic pathway for formation of

Abstract The conversion of the cyclophosphamide intermediate metabolite 4-hydroxycyclophosphamide (4-OHCP) to the final cytotoxic metabolite phosphoramide mustard (PAM) is classically assumed to occur via chemical hydrolysis of the phospho-ester bond. Whilst it has been suggested previously that this reaction could be enzyme-catalysed, there was only indirect evidence for this (i.e. formation of the

Abstract Paeoniflorin is the major constituent in extracts of the paeony root, the purpose of the present study was to assess the effects of paeoniflorin on the activities and mRNA expression of the rat hepatic drug-metabolizing enzymes cytochrome P450 (CYP1A2), CYP2C11 and CYP3A1 in vivo. Sprague-Dawley (SD) male rats were treated with paeoniflorin at the dosage of 25, 50 and 100 mg/kg or 0.9% sodium

Abstract The in vitro antitumor activity (e.g. IC50) of anticancer drugs is important for selecting candidate compounds for in vivo drug efficacy study in the early stage of drug discovery. In this study, we investigated the relationship between in vitro IC50 and in vivo EC50 using six heat shock protein 90 (HSP90) inhibitors. IC50 of each compound was calculated from in vitro cell proliferation assays

Abstract Leonurine hydrochloride (LH) is derived from an ingredient of Leonurus japonicus Houtt which is widely used for diseases in women. The influence of LH on the activity of cytochrome P450 (CYPs) enzymes was investigated in this study. The effect of LH on CYPs enzyme activities were studied using the enzyme-selective substrates phenacetin (1A2), coumarin (2A6), diclofenac (2C9), S-mephenytoin

Abstract Chimeric mice are immunodeficient mice in which the majority of the hepatic parenchymal cells are replaced with human hepatocytes. Following intravenous administration of 24 model compounds to control and chimeric mice, human hepatic clearance (CLh) was predicted using the single-species allometric scaling (SSS) method. Predictability of the chimeric mice was better than that of the control

Abstract Nine forms of recombinant cytochrome P450 (P450 or CYP) enzymes were used to study roles of individual P450 enzymes in the oxidation of flavone and some other flavonoids, 4′-hydroxyflavone and 4′-, 3′-, and 2′-methoxyflavones, by human liver microsomes using LC-MS/MS analysis. As has been reported previously , 4′-, 3′-, and 2′-methoxyflavones were preferentially O-demethylated by human liver

Abstract Bovis Calculus Artifactus (BCA) is the main substitute for natural Calculus bovis, a traditional drug in China used to treat high fever, convulsion, and sore throat. The effect of BCA on cytochrome P450 (CYP) activities is unknown. This study was to investigate the effect of BCA on eight rat hepatic microsomal CYPisozymes to evaluate the potential drug interactions using the cocktail approach

Abstract 1. Retrorsine (RTS) is a pyrrolizidine alkaloid (distributed in many medicinal plants) that has significant hepatotoxicity. Here, we aimed to determine the daily variations in RTS hepatotoxicity (chronotoxicity) in mice, and to investigate the role of metabolism in generating RTS chronotoxicity. 2. Acute toxicity and pharmacokinetic studies were performed with mice after RTS administration

Abstract 1. The aim of this study was to compare the in vitro cytotoxic effect of tramadol and M1 metabolite in HepG2 cell line, the underlying mechanism, and PI3K/AKT/mTOR as potential target. 2. Concentrations representing therapeutic level for tramadol (2 µM) and M1 metabolite (0.5 µM) were used. In addition, other increasing concentrations representing higher toxic levels were used (6, 10 µM for

Abstract We evaluated, in vitro, the interactions between cadmium (Cd) and zinc (Zn) during the proliferation and differentiation process using bone MC3T3-E1 cell line. Cells were treated with CdCl2 and/or ZnCl2 for 24 and 48 h and 5 µM CdCl2 was found as low cytotoxic dose and 25 µM ZnCl2 as the best Zn treatment for cell proliferation. Gene expression of some bone markers (Runx2, collagen α1 (Colα1)

Abstract Podophyllotoxin (POD) is a natural compound with antiviral and anticancer activities. The purpose of the present study was to determine the metabolic map of POD in vitro and in vivo. Mouse and human liver microsomes were employed to identify POD metabolites in vitro and recombinant drug-metabolizing enzymes were used to identify the mono-oxygenase enzymes involved in POD metabolism. All in

Abstract Nonclinical metabolite profiling of DS-1971a, a potent selective NaV1.7 inhibitor, was performed to predict human metabolites. After the oral administration of radiolabelled DS-1971a, the predominant metabolite in mouse plasma was M4, a monoxide at the pyrimidine ring, while the major metabolites with the first and second highest exposure in monkey plasma were M2, a monoxide at the cyclohexane

Abstract Sulfotransferases (SULTs) are phase II detoxification enzymes that is involved in the biotransformation of many compounds including tobacco carcinogens. A polymorphism in the SULT1A1 (Arg213His) gene results in reduced enzyme activity. We investigated the association between the SULT1A1 (Arg213/His) genotype and lung cancer (LC). This case-control study comprised of 550 cases and controls

Abstract 1. Challenges and opportunities in the field of biotransformation were presented and discussed at the 1st European Biotransformation workshop which was conducted virtually in collaboration with the DMDG 27 January 2021. Here we summarize the presentations and discussions from this workshop. The following topics were covered: 2. Needs for radiolabel for IND filing versus quantitation without

Abstract Intra-tumoral (I-TUMOR) delivery is being widely explored for novel anti-cancer agents. This route is anticipated to result in high tumor concentrations leading to better efficacy and safety. Prediction of human systemic pharmacokinetics (PK) from non-clinical species facilitates understanding of pharmacokinetic-pharmacodynamic relationships, efficient dose selection, and risk assessment of

Abstract Lamotrigine is a phenyltriazine anticonvulsant used to treat epilepsy and bipolar disorder, with species-dependent metabolic profiles. In this study, we investigated metabolism of lamotrigine in chimeric NOG-TKm30 mice transplanted with human hepatocytes (humanised-liver mice). Substantial lamotrigine N2-glucuronidation activities were observed in the liver microsomes from humanised-liver

Abstract The disposition of radioactivity following subcutaneous 14C-razuprotafib, a Tie2 activator, was explored in multiple species. The absorption and clearance of razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.36). In pigmented

Abstract Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity.The aims of this study is to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with hematological malignancies. A total of 89 patients received an initial

Abstract Organic anion-transporting polypeptide (OATP) 2B1 plays a critical role in the intestinal absorption of substrate drugs. Apple juice reportedly interacts with OATP2B1 substrate drugs. The purpose of this study was to investigate the effect of two apple polyphenols, phloretin and phloridzin, on OATP2B1-mediated substrate transport in vitro and to evaluate the effect of phloretin on rosuvastatin

Abstract miR-199a-5p is an important regulator of many biological processes. However, whether and how CYP enzymes are regulated by miR-199a-5p are unknown. Here, we aimed to investigate a potential role of mmu-miR-199a-5p in regulating CYP2 enzymes. Regulatory effects of mmu-miR-199a-5p on CYP expression were assessed in mouse AML-12 hepatocytes. Metabolic activity of CYP2B10 was probed using cyclophosphamide

Abstract 1. Variability of the unbound fraction in plasma (fu) between labs, methods and conditions is known to exist. Variability and uncertainty of this parameter influence predictions of the overall pharmacokinetics of drug candidates and might jeopardize safety in early clinical trials. Objectives of this study were to evaluate the variability of human in vitro fu-estimates between labs for a range

Abstract We explored the inhibitory effect of ginsenoside compound K (CK), 20(S)-protopanaxadiol (PPD), and 20(S)-protopanaxatriol (PPT) on six UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) activities in human liver microsomes (HLMs) and ten UGT enzyme (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B10, 2B15, and 2B17) activities in recombinant UGT isoforms. PPD was a potent inhibitor of UGT1A3 activity

Abstract Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug - drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin. Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19 and CYP3A4, only has

Abstract S-Carboxymethyl-l-cysteine is a mucolytic agent used as adjunctive therapy in the treatment of respiratory disorders. Various mechanisms of action have been proposed but few studies have attempted to link the required in vitro concentrations with those achieved actually in vivo during clinical therapy. The data from several published studies has been re-analysed by WinNonlin using non-compartmental

Abstract The effect of 4-O-galloylalbiflorin on the activity of cytochrome P450 enzymes (CYP450s) is an important factor that may induce drug-drug interaction. The effect of 4-O-galloylalbiflorin on the activity of CYP450s was evaluated in the presence of 0, 2.5, 5, 10, 25, 50, and 100 μM 4-O-galloylalbiflorin in pooled human liver microsomes. The inhibition model and corresponding parameters were

Abstract To compare drug–drug interaction (DDI) between tacrolimus and different formulations of phenobarbital in paediatrics and adults. Physiologically based pharmacokinetics (PBPK) models were used to evaluate DDI between phenobarbital (oral (p.o.) and intravenous (i.v.) formulations) and tacrolimus in paediatrics and adults. All dosing regimens were maintained for 7 days. Compared to i.v. phenobarbital

Abstract A challenge in the development of novel 18F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the 18F radioisotope. Metabolic loss of 18F from PET probes in vivo can lead to misleading biodistribution data as displaced 18F can accumulate in various tissues. In this study we report on in vitro hepatic microsomal metabolism

Abstract 8‐[(1H‐1,2,3‐benzotriazol‐1‐yl)amino]octanoic acid (8-BOA) was recently identified as a selective and potent mechanism-based inactivator (MBI) of breast cancer-associated CYP4Z1 and exhibited favourable inhibitory activity in vitro, thus meriting in vivo characterization. The pharmacokinetics and metabolism of 8-BOA in rats was examined after a single IV bolus dose of 10 mg/kg. A biphasic

Abstract Rhubarb, a famous traditional Chinese medicine, shows a wide range of physiological activities and pharmacological benefits. Rhubarb anthraquinones are perceived as the pharmacologically active compounds of Rhubarb, and understanding metabolism of them is crucial to assure safety and effectiveness of clinical application. In this study, the pharmacokinetics, tissue distribution and excretion

Abstract The aim of the present study was to investigate the effect of naringenin (4,5,7-trihydroxy flavonone) on the pharmacokinetics of metoprolol, a substrate of Cytochrome P-450 3A4 (CYP3A4), CYP2C9, and CYP2D6 in rats. Male Wistar rats were treated orally with metoprolol (30 mg/kg) alone and in combination with naringenin (25, 50, and 100 mg/kg) once daily for 15 consecutive days. The plasma concentrations

Abstract FXIa-6f is a high affinity, orally bioavailable macrocyclic FXIa inhibitor with antithrombotic activity in preclinical species. The objectives of this study were to characterize the in vitro metabolism, determine circulating metabolites in pre-clinical species, and examine the disposition of the compound in a bile duct-cannulated rat study (BDC) study to inform clinical development of the

Abstract Statins, the standard treatment for hypercholesterolaemia, among the most widely prescribed, have been associated with side effects, including statin intolerance. The aim of this study was to determine the background prevalence of SLCO1B1 SNVs in a randomly selected sample and to investigate if there are associations between SLCO1B1 SNVs and hypercholesterolaemia patients on statin therapy

Abstract Venlafaxine (VLF), an antidepressant agent, is widely used to combat major depressive disorders, particularly for the treatment of selective serotonin reuptake inhibitor-resistant depression. VLF has been shown to cause liver injury. The present study aimed to investigate the metabolic activation of VLF and explore the mechanisms of hepatotoxicity induced by VLF. One glutathione (GSH) conjugate

Abstract Fluorofenidone (AKF-PD) is an analog of pirfenidone and shows stronger antifibrotic 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

Abstract The induction of cytochrome P450s can result in reduced drug efficacy and lead to potential drug–drug interactions. The xenoreceptors—aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR)—play key roles in CYP induction by xenobiotics. In order to be able to rapidly screen for the induction of three enzymes (CYP1A1, CYP2B6, and CYP3A4), we generated

Abstract It is important to predict drug-drug interactions via inhibition of intestinal cytochrome P450 3A (CYP3A) which is a determinant of bioavailability of orally administered CYP3A substrates. However, inhibitory effects of macrolide antibiotics on CYP3A-mediated metabolism are not entirely identical between humans and rodents. We investigated the effects of macrolide antibiotics, clarithromycin

Abstract We developed an assay system to evaluate the cytochrome P450 (CYP) 3A4-inhibitory activity of compounds, taking account of their cellular permeability, using intestine-derived cell lines pre-treated with the CYP3A4 inducer 1α,25-dihydroxy-vitamin D3 (250 nM). Ketoconazole (KTZ), saquinavir (SQV), naringin, naringenin (NGE), bergamottin (BG), 6',7'-dihydroxybergamottin (DHBG), epigallocatechin

Abstract A common problem in many cancers is the resistance of some patients to common drugs or relapse. Hypoalbuminemia has been reported in some of resistant cancer patients. This article evaluates the usefulness of albumin in the treatment of drug-resistant cancers with hypoalbuminemia based on available evidences. Rapid metabolism and drug excretion from the body is one of the causes of drug resistance

Abstract We evaluated the in vitro drug–drug interaction (DDI) potential of enerisant (TS-091), a histamine H3 receptor antagonist/inverse agonist, mediated by cytochrome P450 (CYP) and transporters, as well as the pharmacokinetics of enerisant in healthy male subjects. Enerisant did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and did not induce CYP1A2, CYP2B6

Abstract The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [14C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively. Pictilisib was rapidly absorbed with Tmax less than 2 h across species. In systemic circulation

Abstract Esculetin is the main active ingredient isolated from Artemisia montana (Nakai) Pamp. and Euphorbia lathyris L. The present study investigated the oral bioavailability and pharmacokinetics of esculetin in rats, following intravenous and oral administration. Twenty Sprague-Dawley rats were randomly assigned to receive 10 mg/kg of esculetin either by the intravenous or oral route. Plasma concentrations

Abstract Diabetes mellitus is a chronic metabolic disorder with multiple complications, patients who receive metformin may have a simultaneous intake of herbal medicine containing rutaecarpine due to cardiovascular protection and hypolipidemic effects of rutaecarpine. There might be drug interactions between metformin and rutaecarpine. This study aimed to investigate the effects of rutaecarpine on

Abstract Phenolic benzotriazoles are ultraviolet-light absorbers used in a variety of industrial and consumer applications. We investigated the toxicokinetic behaviour of 9 compounds, covering unsubstituted, monosubstituted, disubstituted, and trisubstituted compounds, following a single gavage (30 and 300 mg/kg) and intravenous (IV) (2.25 mg/kg) administration in male rats. Following IV administration

Abstract 1. Non-essential heavy metals such as mercury (Hg), arsenic (As), cadmium (Cd), and aluminium (Al) are useless to organisms and have shown extensive toxic effects. Previous studies show that two main molecular mechanisms of metal toxicity are oxidative stress and metal-metal interaction which can disrupt metal homeostasis. 2. In this paper, we mainly illustrate metal toxicity and metal-metal

Abstract Cyclosporin a (CsA) was characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability. In this study, we aimed to identify the association of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms with CsA concentrations in patients with allogeneic haematopoietic cell transplantation (allo-HSCT) based on the route of administration. A total of 40

Abstract We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of valproic acid (VPA) in paediatric epilepsy patients. Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined. Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related

Abstract Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear. The present study aimed to investigate the metabolic activation of ZOL in vitro and in vivo. ZOL-derived glutathione (GSH) and N-acetyl cysteine (NAC)

Abstract The study was conducted to evaluate the frequency of polymorphisms in GSTM1 and GSTT1 genes in patients with breast cancer compared with individuals without history of cancer, and the association of these polymorphisms with clinical/epidemiological parameters. There were evaluated 752 women (219 patients and 533 controls). Molecular analysis was performed by the Polymerase Chain Reaction (PCR)

Abstract Deferiprone (DFP) is a metal chelating agent generally used to treat patients with thalassemia, due to iron overload in clinical settings. Studies have revealed that long-term use of DFP can induce hepatotoxicity, however, mechanisms of its toxic action remain unclear. The present studies are aimed to characterize the reactive metabolite of DFP, to define the metabolic pathway, and to determine

Abstract p-Toluic acid, a metabolite of organic solvent xylene, has a high reported no‐observed‐effect level (NOEL, 1000 mg/kg) in rats, possibly because of direct glycine conjugation to methylhippuric acid. In this study, plasma levels of p-toluic acid and its glycine conjugate in mice and humanised-liver mice were evaluated after oral administrations. Although rapid conversion of p-toluic acid to

Abstract Colchicine is widely investigated for cardioprotection of COVID-19 patients since it can prevent the phenomenon of ‘cytokine storm’ and may reduce the complications arising from COVID-19. Despite the potentially beneficial effects of colchicine, there is no consensus on the appropriate dosage regimen and numerous schemes are currently used. In this study, simulations were performed to identify

Abstract Effects of cholecalciferol (VitD3) and calcitriol (1,25-VitD3), on the expression and function of major vitamin D metabolizing enzymes (cytochrome P450 [CYP]2R1, CYP24A1) and select drug transport pathways (ABCB1/P-gp, SLCO4C1/OATP4C1) were evaluated in human kidney proximal tubule epithelial cells (hPTECs) under normal and uraemic serum conditions. hPTECs were incubated with 10% normal or

Abstract Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. The potential of trazpiroben to act as a perpetrator or a victim for cytochrome P450 (CYP)- or transporter- mediated drug–drug interactions (DDIs) was evaluated following the latest regulatory guidelines. In vitro studies revealed that trazpiroben

Abstract 1. Iris tectorum Maxim is a traditional herbal medicine that has been used to treat cancer, abdominal distension, hepatic cirrhosis, and inflammatory diseases. How I. tectorum Maxim is metabolised and the mechanistic basis for its pharmacological activity remain to be defined. 2. This study was designed to clarify the metabolism of I. tectorum Maxim and to explore the mechanistic basis for

Abstract Ethylene glycol 2-ethylhexyl ether (EGEHE) is a solvent used in a variety of applications. We report disposition and metabolism of EGEHE following a single gavage or dermal administration of 50, 150 or 500 mg/kg [14C]EGEHE in rats and mice and in vitro in rat hepatocytes. EGEHE was cleared rapidly in rat hepatocytes (half-life ∼4 min) with no sex difference. EGEHE was well- and moderately

Abstract The UPLC-MS/MS method was established with good precision, accuracy and stability to determine the concentrations of TPL in biological samples, such as heart, liver, spleen, lung, kidney, plasma and joint. After being made into microspheres, TPL can stay in the joint tissue for a long time, further reducing the number of times joint cavity administration, and its sustained release effect was