Assessing the relative contribution of CYP3A-and P-gp-mediated pathways to the overall disposition and drug-drug interaction of dabigatran etexilate using a comprehensive mechanistic physiological-based pharmacokinetic model.

Dabigatran etexilate (DABE) is a clinical probe substrate for studying drug-drug interaction (DDI) through an intestinal P-glycoprotein (P-gp). A recent study, however, has suggested a potentially significant involvement of CYP3A-mediated oxidative metabolism of DABE and its intermediate monoester BIBR0951 in DDI following microdose administration of DABE. In this study, the relative significance of CYP3A- and P-gp-mediated pathways to the overall disposition of DABE has been explored using mechanistic physiologically based pharmacokinetic (PBPK) modeling approach.

Predicting molecular mechanism of silymarin-potentiated diclofenac toxicity: Insight from molecular docking.

Silymarin was shown to enhance diclofenac toxicity by inducing the loss of mitochondrial membrane permeability (MMP) in Caco-2 cells, independent of endoplasmic reticulum stress. This study employed molecular docking to further investigate the potential interaction between silymarin and specific mitochondrial proteins involved in the loss of mitochondria integrity, aiming to elucidate the underlying mechanism of potentiation. The target proteins for our docking analysis included mitochondrial complex I and III, voltage-dependent anion-selective channel (VDAC), and cyclophilin D (CypD).

The Potentially Significant Role of CYP3A-Mediated Oxidative Metabolism of Dabigatran Etexilate and Its Intermediate Metabolites in Drug-Drug Interaction Assessments Using Microdose Dabigatran Etexilate.

Dabigatran etexilate (DABE), a double ester prodrug of dabigatran, is a probe substrate of intestinal P-glycoprotein (P-gp) commonly used in clinical drug-drug interaction (DDI) studies. When compared with its therapeutic dose at 150 mg, microdose DABE (375 µg) showed approximately 2-fold higher in DDI magnitudes with CYP3A/P-gp inhibitors. In this study, we conducted several metabolism studies to demonstrate that DABE, at a theoretical gut concentration after microdosing, significantly underwent NADPH-dependent oxidation (~40%-50%) in parallel to carboxylesterase-mediated hydrolysis in human intestinal microsomes.

Quaternization of high molecular weight chitosan for increasing intestinal drug absorption using Caco-2 cells as an in vitro intestinal model.

Potential use of a quaternized chitosan (MW 600 kDa) with 65% of 3-chloro-2-hydroxypropyltrimethylammonium (600-HPTChC) as an absorptive enhancer was investigated in Caco-2 monolayers. 600-HPTChC (0.005% w/v) quickly reduced transepithelial electrical resistance (TEER) to the maximum level in 40 min with full recovery within 6 h after removal.

Different protective capability of chlorogenic acid and quercetin against indomethacin-induced gastrointestinal ulceration.

Objectives: The study compared the protective effects against indomethacin-induced GI ulceration of chlorogenic acid with quercetin in rats.

Methods: Rats were orally given chlorogenic acid or quercetin (100 mg/kg; 5 days), followed by indomethacin (40 mg/kg; single dose). After 24 h, GI tissues were assessed for histopathological damages, then analysed by ELISA and western blot methods.

Anticancer and chemosensitizing activities of stilbenoids from three orchid species.

Recently, we have isolated and identified several bioactive flavonoids and stilbenoids with potential anticancer activity from Thai orchids. In this study, we further investigated the cytotoxic and chemosensitizing activities of these phytochemicals (namely, pinocembrin, cardamonin, isalpinin, galangin, pinosylvin monomethyl ether, 2,3'-dihydroxy-5'-methoxystilbene, (E)-2,5'-dihydroxy-2'-(4-hydroxybenzyl)-3'-methoxystilbene, 2,3-dihydroxy-3',5'-dimethoxystilbene, 2,3'-dihydroxy-5,5'-dimethoxystilbene, 3,4'-dihydroxy-5-methoxystilbene and batatasin III) against breast cancer MCF7 cells and its two multidrug resistant (MDR) sublines (MCF7/DOX and MCF7/MX). Cytotoxicity was determined with MTT assay for the estimation of the half maximal cytotoxic concentrations (IC).

Three new cytotoxic stilbene dimers from .

Three new stilbene dimers, paphiodianthins A-C (1-3), and nine known stilbenes, lignan and flavonoids (4-12) were isolated from the roots and leaves of (Orchidaceae). The structures of new compounds were elucidated from their NMR, HRESIMS and IR spectroscopic data. Cytotoxic activity of all isolated compounds was evaluated by MTT assay against two human cancer cell lines (MCF-7, Caco-2), doxorubicin-resistant and mitoxantrone-resistant MCF-7 sublines, as well as a normal cell line (NIH/3T3).

Coumaroyltyramine Enhances Indomethacin- and Diclofenac-induced Apoptosis Through Endoplasmic Reticulum Stress-dependent Mechanism in MCF-7 Cells.

Background/aim: The anticancer potential of indomethacin and diclofenac has been reported against several types of cancer cells. In this study, we investigated the enhancement effect of a coumaric acid derivative found in some Piper plants, N-trans-p-coumaroyltyramine (TCT) on indomethacin and diclofenac cytotoxicity in breast cancer cells.

Materials And Methods: MCF-7 and mitoxantrone-resistant MCF-7 (MCF-7/MX) cancer cells were treated with indomethacin or diclofenac in the presence of TCT for 48 h.

Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach.

Ageing and chronic kidney disease (CKD) affect pharmacokinetic (PK) parameters. Since mechanisms are related and remain unclear, cytochrome P450 (CYP) 3A and drug transporter activities were investigated in the elderly with or without CKD and compared to healthy adults using a microdose cocktail. Healthy young participants ( = 20), healthy elderly participants ( = 16) and elderly patients with CKD ( = 17) received, in study period 1, a single dose of microdose cocktail probe containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin.

Apoptosis Inducing Activity of Rhinacanthin-C in Doxorubicin-Resistant Breast Cancer MCF-7 Cells.

Rhinacanthin-C is a natural bioactive naphthoquinone ester with potential chemotherapeutic value in cancer treatment. In this study, we investigated its apoptotic induction ability and the involved mechanisms through the mitogen-activated protein kinases (MAPK) and protein kinase B/glycogen synthase kinase-3β/nuclear factor erythroid 2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathways in doxorubicin-resistant breast cancer MCF-7 (MCF-7/DOX) cells. Our 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that rhinacanthin-C (3-28 µM) significantly decreased the viability of MCF-7/DOX cells and potentiated hydrogen peroxide cytotoxicity.

Development and Qualification of a Physiologically Based Pharmacokinetic Model of Finasteride and Minoxidil Following Scalp Application.

In this study, we aimed to develop and qualify a PBPK model for scalp application using two drugs with marked differences in physicochemical properties and PK profiles. The parameters related to scalp physiology, drug PK, and formulations were incorporated into a Multi-Phase and Multi-Layer (MPML) Mechanistic Dermal Absorption (MechDermA) model within the Simcyp® Simulator V17. The finasteride PBPK model was linked to its effect on dihydrotestosterone (DHT) levels in plasma and scalp using an indirect response model.

and Gene Polymorphisms in a Thai Population.

Introduction: Genetic polymorphisms of drug transporters influence drug transporter activity and alter pharmacokinetic profiles of the drugs. Organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) are important transporters encoded by solute carrier organic anion transporter family member 1B1 () gene and ATP-binding cassette subfamily G member 2 () gene, respectively. Polymorphisms in these genes are associated with increased plasma statins concentrations, statin-induced myopathy and poor response to allopurinol treatment.

Modulation of non-steroidal anti-inflammatory drug-induced, ER stress-mediated apoptosis in Caco-2 cells by different polyphenolic antioxidants: a mechanistic study.

Objectives: Direct scavenging of reactive oxygen species could not prevent ER stress-associated cytotoxicity of indomethacin or diclofenac in Caco-2 cells. This study investigated the effects of three polyphenolic antioxidants epigallocatechin gallate (EGCG), phyllanthin and hypophyllathin in non-steroidal anti-inflammatory drug-induced Caco-2 apoptosis.

Methods: Cells were treated with ER stressors (indomethacin, diclofenac, tunicamycin or thapsigargin) and the polyphenols for up to 72 h.

Pharmacokinetics of nucleoside/nucleotide reverse transcriptase inhibitors for the treatment and prevention of HIV infection.

Introduction: Despite dramatic increases in new drugs and regimens, a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remains the backbone of many regimens to treat HIV.

Area Covered: This article summarizes the pharmacokinetic characteristics of approved NRTIs that are currently in the international treatment and prevention guidelines.

Expert Opinion: Compared to other NRTIs, tenofovir alafenamide fumarate (TAF) is more advantageous in terms of potency and safety.

Natural polyphenols prevent indomethacin-induced and diclofenac-induced Caco-2 cell death by reducing endoplasmic reticulum stress regardless of their direct reactive oxygen species scavenging capacity.

Objectives: Indomethacin (INDO) and diclofenac (DIC) can induce intestinal cell death through induction of oxidative stress-mediated ER stress and mitochondrial dysfunction. This study investigated the cytoprotective potential of 11 polyphenols, namely caffeic acid (CAF), curcumin (CUR), epigallocatechin gallate (EGCG), gallic acid (GAL), hypophyllanthin (HYPO), naringenin (NAR), phyllanthin (PHY), piperine (PIP), quercetin (QUE), rutin (RUT) and silymarin (SLY) against these two NSAIDs in Caco-2 cells.

Methods: Reactive oxygen species (ROS) production was determined with fluorescence spectroscopy using specific probes (DHE, DCFH-DA, HPF).

Rhinacanthin-C Mediated Herb-Drug Interactions with Drug Transporters and Phase I Drug-Metabolizing Enzymes.

Rhinacanthin-C is a major active constituent in (L.) Kurz, a plant widely used in herbal remedies. Its potential for pharmacokinetic herb-drug interaction may exist with drug transporters and drug metabolizing enzymes.

Potential P-glycoprotein-mediated herb-drug interaction of phyllanthin at the intestinal absorptive barrier.

Objectives: This study investigated the absorptive potential of phyllanthin across the polarized Caco-2 monolayers and the potential role of phyllanthin in P-glycoprotein (P-gp)-mediated drug interaction.

Methods: The absorptive potential of phyllanthin was predicted from its apparent permeability (P ) across the Caco-2 monolayers under the pH gradient condition (pH 6.5 -7.

Benzophenones and xanthone derivatives from Garcinia schomburgkiana-induced P-glycoprotein overexpression in human colorectal Caco-2 cells via oxidative stress-mediated mechanisms.

Background: Up-regulation of P-gp is an adaptive survival mechanism of cancer cells from chemotherapy. Three new phytochemicals including two benzophenones, guttiferone K (GK) and oblongifolin C (OC), and a xanthone, isojacaruebin (ISO), are potential anti-cancer agents. However, the capability of these compounds to increase multidrug-resistance (MDR) through P-gp up-regulation in cancer cells has not been reported.

Rhinacanthin-C enhances doxorubicin cytotoxicity via inhibiting the functions of P-glycoprotein and MRP2 in breast cancer cells.

Rhinacanthin-C is a major bioactive naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae). This compound has potential therapeutic value as an anticancer and antiviral agent. In this study, we investigated an enhancement effect of rhinacanthin-C on doxorubicin cytotoxicity in human breast cancer cell lines and the involvement of the ABC drug efflux transporters.

Effects of rhinacanthin-C on function and expression of drug efflux transporters in Caco-2 cells.

Rhinacanthin-C is a bioactive naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae). This compound has potential therapeutic value as an anticancer and antiviral agent. The purposes of this study were to determine the effects of this compound on the function and the expression of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2), using the in vitro model of Caco-2 cells.

Phyllanthin and hypophyllanthin inhibit function of P-gp but not MRP2 in Caco-2 cells.

Objectives: The purposes of this study were to investigate the inhibitory effects of two lignans, phyllanthin and hypophyllanthin, on the function of P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), using the in-vitro model of Caco-2 cells. In addition, the effect of prolonged exposure to these two compounds on the expression of active P-gp was also determined.

Methods: The activity of P-gp and MRP2 was determined in the uptake assays by monitoring the intracellular accumulation of their specific substrates (calcein acetoxymethyl ester and 5(6)-carboxy-2',7'-dichlorofluorescein diacetate, respectively) with fluorescence spectroscopy.

Endothelium-independent effects of phyllanthin and hypophyllanthin on vascular tension.

The purpose of this study was to investigate the modulating effects of phyllanthin and hypophyllanthin on vascular tension, using in the in vitro model of isolated rat aorta. Our results indicated that both phyllanthin and hypophyllanthin significantly relaxed the sustained contraction induced by phenylephrine (PE) in a concentration-dependent manner. In addition, endothelial removal had no significant influence on the vasorelaxation responses of the aortic rings toward these two compounds.

Protective effect of quercetin on hydrogen peroxide-induced tight junction disruption.

Tight junction is a crucial structure in the control of paracellular transport across epithelial/endothelial barriers. This study investigated the protective effect of quercetin against hydrogen peroxide (H(2)O(2))-induced tight junction disruption and hyperpermeability in ECV304 monolayers. Nonlethal concentration of H(2)O(2) (100 micromol/L; 4 hours) decreased expression of the tight junction proteins zonular occudens (ZO)-1 and occludin as well as disrupted the junction structure at the cell border.

Autoxidation of brain homogenates from various animals as measured by thiobarbituric acid assay.

Introduction: The TBARS assay has been well recognized for determination of lipid peroxidation and oxidative injury in biological samples including brain homogenates. In general, the homogenates are freshly prepared using rat brains as the tissue sources. In this study, we compared the rates of spontaneous lipid peroxidation in brain homogenates obtained from bovine, canine, hen, rat, and swine.

Tetrahydrobiopterin protects against guanabenz-mediated inhibition of neuronal nitric-oxide synthase in vitro and in vivo.

It is established that guanabenz inhibits neuronal nitric-oxide (NO) synthase (nNOS) and causes the enhanced proteasomal degradation of nNOS in vivo. Although the time- and NADPH-dependent inhibition of nNOS has been reported in studies where guanabenz was incubated with crude cytosolic preparations of nNOS, the exact mechanism for inhibition is not known. Moreover, even less is known about how the inhibition of nNOS triggers its proteasomal degradation.