P-glycoprotein Inhibitor Research Articles

Delivery of Lutein by Using Modified Burdock Polysaccharide Aggregates: Preparation, Characterization, and In Vitro Release Properties.

Novel self-assembled aggregates of stearic acid (SA)-modified burdock polysaccharide (BP) for loading lutein were constructed, and the release and absorption properties of lutein in the aggregates in simulated gastrointestinal fluid were investigated. Three different degrees of substitution (DS) of SA-BPs were used to embed lutein, resulting in the encapsulation efficiency exceeding 90%. The aggregates were uniformly spherical, with a particle size range of 227-341 nm. XRD analysis revealed that lutein was present in a non-crystalline state within the aggregates. FT-IR and FS analysis demonstrated that lutein was located in the hydrophobic domains of SA-BP. The highest bioavailability of lutein in these aggregates reached 4.36 times that in the unmodified samples. These aggregates were able to remain stable in gastric juice and enhance the release rate of lutein in intestinal fluid. The transport of lutein-loaded SA-BP aggregates in Caco-2 cells competed with P-glycoprotein inhibitors, mainly promoting the transmembrane absorption of lutein through caveolae (or lipid raft)-related and clathrin-dependent endocytosis pathways. The above results suggest that SA-BP aggregates have the potential to be promising carriers for the efficient delivery of hydrophobic lutein.

Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold.

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.

A systematic review of the drug-drug interaction between Statins and Quinolones

BackgroundStatins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction.MethodsThe purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms.ResultsThere were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20–80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800–1500 mg/d, levofloxacin (n = 6) at a dose range of 250–1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors.ConclusionPatients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors.

Analysis of hemorrhagic drug-drug interactions between P-gp inhibitors and direct oral anticoagulants from the FDA Adverse Event Reporting System

ABSTRACT Background Limited understanding exists regarding the hemorrhagic risk resulting from potential interactions between P-glycoprotein (P-gp) inhibitors and direct oral anticoagulants (DOACs). Utilizing the Food and Drug Administration Adverse Event Reporting System (FAERS) data, we analyzed hemorrhagic adverse events (AEs) linked with the co-administration of P-gp inhibitors and DOACs, aiming to offer guidance for their safe and rational use. Methods Hemorrhagic events associated with P-gp inhibitors in combination with DOACs were scrutinized from the FAERS database. Hemorrhagic signals mining was performed by estimating the reported odds ratios (RORs), corroborated by additive and multiplicative models and a combination risk ratio (PRR) model. Results Our analysis covered 4,417,195 cases, revealing 11,967 bleeding events associated with P-gp inhibitors. We observed a significantly higher risk of bleeding with the combination of apixaban and felodipine (ROR 118.84, 95% CI 78.12–180.79, additive model 0.545, multiplicative model 1.253, PRR 22.896 (2450.141)). Moreover, consistent associations were found in the co-administration analyzes of rivaroxaban with dronedarone and diltiazem, and apixaban with losartan, telmisartan, and simvastatin. Conclusion Our FAERS data analysis unveils varying degrees of bleeding risk associated with the co-administration of P-gp inhibitors and DOACs, underscoring the importance of vigilance about them in clinical practice.

Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

Investigating how HIV-1 antiretrovirals differentially behave as substrates and inhibitors of P-glycoprotein via molecular dynamics simulations

HIV-1 can rapidly infect the brain upon initial infection, establishing latent reservoirs that induce neuronal damage and/or death, resulting in HIV-Associated Neurocognitive Disorder. Though anti-HIV-1 antiretrovirals (ARVs) suppress viral load, the blood-brain barrier limits drug access to the brain, largely because of highly expressed efflux proteins like P-glycoprotein (P-gp). While no FDA-approved P-gp inhibitor currently exists, HIV-1 protease inhibitors show promise as partial P-gp inhibitors, potentially enhancing drug delivery to the brain. Herein, we employed docking and molecular dynamics simulations to elucidate key differences in P-gp’s interactions with several antiretrovirals, including protease inhibitors, with known inhibitory or substrate-like behaviors towards P-gp. Our results led us to hypothesize new mechanistic details of small-molecule efflux by and inhibition of P-gp, where the “Lower Pocket” in P-gp’s transmembrane domain serves as the primary initial site for small-molecule binding. Subsequently, this pocket merges with the more traditionally studied drug binding site—the “Upper Pocket”—thus funneling small-molecule drugs, such as ARVs, towards the Upper Pocket for efflux. Furthermore, our results reinforce the understanding that both binding energetics and changes in protein dynamics are crucial in discerning small molecules as non-substrates, substrates, or inhibitors of P-gp. Our findings indicate that interactions between P-gp and inhibitory ARVs induce bridging of transmembrane domain helices, impeding P-gp conformational changes and contributing to the inhibitory behavior of these ARVs. Overall, insights gained in this study could serve to guide the design of future P-gp-targeting therapeutics for a wide range of pathological conditions and diseases, including HIV-1.

Preparation and intestinal absorption mechanism of self-assembled nanoparticles of Herpetospermum caudigerum

In this experiment, the micro-precipitation method was used to prepare self-assembled nanoparticles of Herpetospermum caudigerum Wall.(MP-SAN). The process was optimized using average particle size and polydispersity index(PDI)as evaluation indexes. The mean particle size, PDI,zeta potential, and microstructure of MP-SAN were characterized. The intestinal absorption mechanism of dehydrodiconiferyl alcohol(DA)and herpetrione(Her)in MP-SAN was investigated through single-pass intestinal perfusion in rats. The optimized process parameters for producing MP-SAN were a stirring speed of 800 r·min~(-1),stirring time of 5 min, and rotary evaporation temperature of 40℃. The resulting MP-SAN exhibited a spherical-like structure and uniform morphology, with a mean particle size of(267.63±13.27) nm, a PDI of 0.062 0±0.043 9,and a zeta potential of(-46.18±3.66) mV. The absorption rate constant(K_a)and apparent permeability coefficient(P_(app))of DA in the ileal segment were significantly higher than those in the jejunal segment(P<0.05). However, there was no significant difference in the absorption of Her between the ileal and jejunal segments. Intestinal absorption parameters of DA and Her tended to increase with increasing drug concentration. Specifically, the K_a and P_(app) of DA in MP-SAN in the high-concentration group were significantly higher than those in the low-concentration group(P<0.01). The addition of verapamil, a P-glycoprotein inhibitor, did not significantly affect the intestinal absorption of DA and Her. However, the absorption of both DA and Her in MP-SAN was significantly increased by the addition of indomethacin(P<0.05),suggesting that DA and Her may be substrates for multidrug resistance-associated protein 2.

Hexestrol, an estrogen receptor agonist, inhibits Lassa virus entry.

Lassa virus (LASV) is the causative agent of human Lassa fever which in severe cases manifests as hemorrhagic fever leading to thousands of deaths annually. However, no approved vaccines or antiviral drugs are currently available. Recently, we screened approximately 2,500 compounds using a recombinant vesicular stomatitis virus (VSV) expressing LASV glycoprotein GP (VSV-LASVGP) and identified a P-glycoprotein inhibitor as a potential LASV entry inhibitor. Here, we show that another identified candidate, hexestrol (HES), an estrogen receptor agonist, is also a LASV entry inhibitor. HES inhibited VSV-LASVGP replication with a 50% inhibitory concentration (IC50) of 0.63 µM. Importantly, HES also inhibited authentic LASV replication with IC50 values of 0.31 µM-0.61 µM. Time-of-addition and cell-based membrane fusion assays suggested that HES inhibits the membrane fusion step during virus entry. Alternative estrogen receptor agonists did not inhibit VSV-LASVGP replication, suggesting that the estrogen receptor itself is unlikely to be involved in the antiviral activity of HES. Generation of a HES-resistant mutant revealed that the phenylalanine at amino acid position 446 (F446) of LASVGP, which is located in the transmembrane region, conferred resistance to HES. Although mutation of F446 enhanced the membrane fusion activity of LASVGP, it exhibited reduced VSV-LASVGP replication, most likely due to the instability of the pre-fusion state of LASVGP. Collectively, our results demonstrated that HES is a promising anti-LASV drug that acts by inhibiting the membrane fusion step of LASV entry. This study also highlights the importance of the LASVGP transmembrane region as a target for anti-LASV drugs.IMPORTANCELassa virus (LASV), the causative agent of Lassa fever, is the most devastating mammarenavirus with respect to its impact on public health in West Africa. However, no approved antiviral drugs or vaccines are currently available. Here, we identified hexestrol (HES), an estrogen receptor agonist, as the potential antiviral candidate drug. We showed that the estrogen receptor itself is not involved in the antiviral activity. HES directly bound to LASVGP and blocked membrane fusion, thereby inhibiting LASV infection. Through the generation of a HES-resistant virus, we found that phenylalanine at position 446 (F446) within the LASVGP transmembrane region plays a crucial role in the antiviral activity of HES. The mutation at F446 caused reduced virus replication, likely due to the instability of the pre-fusion state of LASVGP. These findings highlight the potential of HES as a promising candidate for the development of antiviral compounds targeting LASV.

Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors

Paclitaxel (PTX) is considered the blockbuster chemotherapy treatment for cancer. Paclitaxel's (PTX) oral administration has proven to be extremely difficult, mostly because of its susceptibility to intestinal P-glycoprotein (P-gp) and cytochrome P450 (CYP3A4). The concurrent local inhibition of intestinal P-gp and CYP3A4 is a promising approach to improve the oral bioavailability of paclitaxel while avoiding potential unfavorable side effects of their systemic inhibition. Herein, we report the rational design and evaluation of novel dual potent inhibitors of P-gp and CYP3A4 using an anthranilamide derivative tariquidar as a starting point for their structural optimizations. Compound 14f, bearing N-imidazolylbenzyl side chain, was found to have potent and selective P-gp (EC50 = 28 nM) and CYP3A4 (IC50 = 223 nM) inhibitory activities with low absorption potential (Papp (A-to-B) <0.06). In vivo, inhibitor 14f improved the oral absorption of paclitaxel by 6 times in mice and by 30 times in rats as compared to vehicle, while 14f itself remained poorly absorbed. Compound 14f, possessing dual P-gp and CYP3A4 inhibitory activities, offered additional enhancement in paclitaxel oral absorption compared to tariquidar in mice. Evaluating the CYP effect of 14f on oral absorption of paclitaxel requires considering the variations in CYP expression between animal species. This study provides further medicinal chemistry advice on strategies for resolving concerns with the oral administration of chemotherapeutic agents.

P-gp inhibition and enhanced oral bioavailability of amikacin Sulfate: A novel approach using Thiolated Chito-PEGylated Lipidic Hybrids

This study aimed to develop oral lipidic hybrids of amikacin sulfate (AMK), incorporating thiolated chitosan as a P-glycoprotein (P-gp) inhibitor to enhance intestinal absorptivity and bioavailability. Three formulations were designed: PEGylated Liposomes, Chitosan-functionalized PEGylated (Chito-PEGylated) Lipidic Hybrids, and Thiolated Chito-PEGylated Lipidic Hybrids. The physical characteristics of nanovesicles were assessed. Ex-vivo permeation and confocal laser scanning microscopy (CLSM) studies were conducted to evaluate the formulations’ potential to enhance AMK intestinal permeability. In-vivo pharmacokinetic studies in rats and histological/biochemical investigations assessed the safety profile and oral bioavailability. The AMK-loaded Thiolated Chito-PEGylated Lipidic Hybrids exhibited favorable physical characteristics, higher ex-vivo permeation parameters, and verified P-gp inhibition via CLSM. They demonstrated heightened oral bioavailability (68.62% absolute bioavailability) and a sufficient safety profile. Relative bioavailability was significantly higher (1556.3% and 448.79%) compared to PEGylated Liposomes and Chito-PEGylated Lipidic Hybrids, respectively, indicating remarkable oral AMK delivery with fewer doses, reduced side effects, and enhanced patient compliance.

Preparation and characterization of azelnidipine-loaded D-α-tocopheryl polyethylene glycol succinate (TPGS) / solutol micelles

Azelnidipine is a calcium-channel antagonist classified as a “class 2” drug with high permeability and low aqueous solubility. It is used in the treatment of angina pectoris and hypertension without reflex tachycardia. Improvement of the solubility of azelnidipine and increasing drug’s bioavailability can be achieved through the drug encapsulation in solutol / D-α-tocopheryl polyethylene glycol succinate (TPGS) micelles. Six formulas were prepared by direct disso¬lution after using different amounts of solutol and TPGS. TPGS and solutol act as solubilizers, permeation enhancers, and P-glycoprotein inhibitors. The particle size, particle size distribution, zeta potential, and entrapment efficiency were determined. Depending on particle size and entrapment efficiency, formula #6 was selected and subjected to in vitro dilution stability and in vitro release studies. The results obtained showed that formula #6 was the best formula, with a high entrapment efficiency percentage equal to 86.5%±0.58% and a small particle size equal to 21.9±7.75 nm that did not change significantly after dilution up to 100-fold; a fact that reveals the high thermodynamic and kinetic stability of the optimum formula. The formula #6 release profile showed a controlled release of the drug from micelles when compared to plain drug release. Based on these results, polymeric nanomicelles are regarded as a promising delivery system for azelnidipine.

Spice components as modulating agents of P-glycoprotein - An in silico study.

P-glycoprotein acts as a protective barrier against xenobiotics and cellular toxicants in the human body while playing an important role in drug transportation in many organs. Overexpression of p-glycoprotein can lead to a decrease in the absorption of many drugs. After screening, 33 phytochemicals from 25 spices were selected for docking with p-glycoprotein to detect some naturally occurring p-glycoprotein inhibitors to modulate multidrug resistance. Absorption, distribution, metabolism, excretion, and toxicity prediction and drug-like properties of those ligands were investigated from pkCSM, Molinspiration, and SwissADME software, followed by molecular docking study and molecular dynamic simulation on BIOVIA Discovery Studio. These 33 phytochemicals met the criteria of p-glycoprotein inhibitor as much as the reference drug verapamil. Pandamarilactone-31 showed the highest binding affinity for p-glycoprotein, acting as the lead p-glycoprotein inhibitor, followed by α-D-fructofuranoside methyl, sesamolinol, and nigellidine.

Nirmatrelvir/ritonavir treatment of patients with COVID-19 taking tacrolimus: case series describing the results of drug-drug interactions.

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.

Polyvinylpyrrolidone Assisted One-Pot Synthesis of Size-Tunable Cocktail Nanodrug for Multifunctional Combat of Cancer.

The in vivo barriers and multidrug resistance (MDR) are well recognized as great challenges for the fulfillment of antitumor effects of current drugs, which calls for the development of novel therapeutic agents and innovative drug delivery strategies. Nanodrug (ND) combining multiple drugs with distinct modes of action holes the potential to circumvent these challenges, while the introduction of photothermal therapy (PTT) can give further significantly enhanced efficacy in cancer therapy. However, facile preparation of ND which contains dual drugs and photothermal capability with effective cancer treatment ability has rarely been reported. In this study, we selected curcumin (Cur) and doxorubicin (Dox) as two model drugs for the creation of a cocktail ND (Cur-Dox ND). We utilized polyvinylpyrrolidone (PVP) as a stabilizer and regulator to prepare Cur-Dox ND in a straightforward one-pot method. The size of the resulting Cur-Dox ND can be easily adjusted by tuning the charged ratios. It was noted that both loaded drugs in Cur-Dox ND can realize their functions in the same target cell. Especially, the P-glycoprotein inhibition effect of Cur can synergistically cooperate with Dox, leading to enhanced inhibition of 4T1 cancer cells. Furthermore, Cur-Dox ND exhibited pH-responsive dissociation of loaded drugs and a robust photothermal translation capacity to realize multifunctional combat of cancer for photothermal enhanced anticancer performance. We further demonstrated that this effect can also be realized in 3D multicellular model, which possibly attributed to its superior drug penetration as well as photothermal-enhanced cellular uptake and drug release. In summary, Cur-Dox ND might be a promising ND for better cancer therapy.

Gastrointestinal bleeding in elderly patients with atrial fibrillation: prespecified All Nippon Atrial Fibrillation in the Elderly (ANAFIE) Registry subgroup analysis

Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88–1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

Effects of Quinidine or Rifampin Co-administration on the Single-Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants.

This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300mg every 8hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.

Enzalutamide: Understanding and Managing Drug Interactions to Improve Patient Safety and Drug Efficacy.

Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy.

Design and synthesis of novel imidazole-chalcone derivatives as microtubule protein polymerization inhibitors to treat cervical cancer and reverse cisplatin resistance

Using the licochalcone moiety as a lead compound scaffold, 16 novel imidazole-chalcone derivatives were designed and synthesized as microtubule protein polymerization inhibitors. The proliferation inhibitory activities of the derivatives against SiHa (human cervical squamous cell carcinoma), C-33A (human cervical cancer), HeLa (human cervical cancer), HeLa/DDP (cisplatin-resistant human cervical cancer), and H8 (human cervical epithelial immortalized) cells were evaluated. Compound 5a exhibited significant anticancer activity with IC50 values ranging from 2.28 to 7.77 μM and a resistance index (RI) of 1.63, while showing minimal toxicity to normal H8 cells. When compound 5a was coadministered with cisplatin, the RI of cisplatin to HeLa/DDP cells decreased from 6.04 to 2.01, while compound 5a enhanced the fluorescence intensity of rhodamine 123 in HeLa/DDP cells. Further studies demonstrated that compound 5a arrested cells at the G2/M phase, induced apoptosis, reduced colony formation, inhibited cell migration, and inhibited cell invasion. Preliminary mechanistic studies revealed that compound 5a decreased the immunofluorescence intensity of α-/β-tubulin in cancer cells, reduced the expression of polymerized α-/β-tubulin, and increased the expression of depolymerized α-/β-tubulin. Additionally, the molecular docking results demonstrate that compound 5a can interact with the tubulin colchicine binding site and generate multiple types of interactions. These results suggested that compound 5a has anticancer effects and significantly reverses cervical cancer resistance to cisplatin, which may be related to its inhibition of microtubule and P-glycoprotein (P-gp) activity.

Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors.

Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n=748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.

Formulation and bioavailability studies on orodispersible tablets containing standardized extracts of Glycyrrhiza glabra, Curcuma longa and Piper nigrum

BackgroundGlycyrrhizin, Curcumin and Piperine indicated good antiasthamatic properties owing to their ability to inhibit airways constriction and anti-inflammatory properties. Orodispersible tablets have advantage of faster drug release and has patient compliance in asthmatic patients. Hypothesis / PurposeTo develop an orodispersible polyherbal tablets using the standardized extracts of Glycyrrhiza glabra, Curcuma longa and Piper nigrum with respect to glycyrrhizin, curcumin and piperine respectively and evaluate bioavailability of the markers from the formulation. MethodsAlcoholic extracts of G. glabra, C. longa, and P. nigrum were standardized using HPTLC for glycyrrhizin, curcumin, and piperine content, respectively. The orodispersible tablet formulation was created and standardized for curcumin (50 mg), glycyrrhizin (75 mg), and piperine (2.5 mg) per tablet, using the HPTLC method. The absolute Bioavailability studies were conducted for glycyrrhetinic acid and curcumin in rats by administering pure marker compounds intravenously (2 mg/kg b.w) and orally (10 mg/kg b.w.), followed by determining relative bioavailability through oral administration of the orodispersible tablet formulations. ResultsOrodispersible tablets could be successfully developed using the standardized extracts. The HPTLC bioanalytical method was developed and validated as per M 10 guideline and results were in accordance to specifications. The bioavailability studies in rats indicated absolute bioavailability of Glycyrrhetinic acid and Curcumin to be 20.35 and 2.57% respectively and relative bioavailabilities of orodispersible formulation F1 were found to be 75 and 38.67%. ConclusionA standardized orodispersible formulation can be a better option for asthma patients. The low absolute bioavailability of curcumin was significantly (P<0.05) increased in both the formulations F1 and F2. This may be attributed to the extracts containing saponin glycosides like Glycyrrhizin aiding into greater dissolution of curcumin. Formulation with piperine (F1) showed significant increase in bioavailability is due to inhibition of human P-glycoprotein, cytochrome P450 3A4 (CYP3A4) and increase secretion of bile acids.