Article
Medicine, Research & Experimental
Lara Garcia-Varela, Manuel Rodriguez-Perez, Antia Custodia, Rodrigo Moraga-Amaro, Nicola A. Colabufo, Pablo Aguiar, Tomas Sobrino, Rudi A. J. O. Dierckx, Aren van Waarde, Philip H. Elsinga, Gert Luurtsema
Summary: P-glycoprotein (P-gp) inducer MC111 increases P-gp functionality in the whole brain of rats, potentially offering a treatment option for neurodegenerative diseases.
MOLECULAR PHARMACEUTICS
(2021)
Article
Pharmacology & Pharmacy
Casey-Tyler Berezin, Nikolas Bergum, Glenda M. Torres Lopez, Jozsef Vigh
Summary: Opioids are effective analgesics, but their dangerous side effects need to be considered. Research on opioid pharmacokinetics provides crucial information on drug effects. This study found that morphine accumulates in the mouse retina at higher concentrations than in the brain and that reduced P-gp expression may be the cause. P-gp was identified as the main opioid transporter at the blood-retina barrier, and its expression correlated with morphine concentration in the retina.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Sarah Lazzaro, Mark A. West, Soraya Eatemadpour, Bo Feng, Manthena V. S. Varma, A. David Rodrigues, Csilla Temesszentandrasi-Ambrus, Peter Kovacs-Hajdu, Zsuzsanna Nerada, Zsuzsanna Gaborik, Chester Costales
Summary: This study evaluated the impact of potential IC50 discrepancies between two commonly utilized assay methods (cell-based and vesicle-based) on P-gp. Non-P-gp substrates showed good correlation between the two methods, while IC50s of P-gp substrates were lower in the vesicle assays. IC50s obtained from two independent laboratories using the same method showed good correlation.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Neurosciences
Yuying Cen, Yuheng Shan, Jiahua Zhao, Xiaojiao Xu, Zhiyong Nie, Jiatang Zhang
Summary: This study aimed to investigate the impact of major transporters at the blood-brain barrier and blood-cerebrospinal fluid barrier on the pharmacokinetics of levofloxacin in rats. The results showed that the efflux of levofloxacin from the central nervous system involves multi-drug resistance-associated proteins, breast cancer resistance protein, and organic anion transporters. The concentrations of levofloxacin in cerebrospinal fluid can be used as a surrogate to predict the concentrations inside the brain parenchyma.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Review
Biochemistry & Molecular Biology
Bikram Khadka, Jae-Young Lee, Eui Kyun Park, Ki-Taek Kim, Jong-Sup Bae
Summary: Natural compounds can interact with drugs during the treatment of brain disorders, affecting the pharmacokinetic properties and cellular transport of drugs, potentially leading to synergistic toxicity or impeding drug interactions. Challenges arising from these natural compound-drug interactions and recent research approaches are discussed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Diogo Henrique Kita, Gisele Alves de Andrade, Juliana Morais Missina, Kahoana Postal, Viktor Kalbermatter Boell, Francielli Sousa Santana, Ingrid Fatima Zattoni, Isadora da Silva Zanzarini, Vivian Rotuno Moure, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Emanuel Maltempi de Souza, David A. Mitchell, Suresh Ambudkar, Giovana Gioppo Nunes, Glaucio Valdameri
Summary: The study found that polyoxovanadates can serve as inhibitors of ABC drug transporters, selectively inhibiting P-glycoprotein with V-10 and V-18 being the most promising compounds.
Review
Multidisciplinary Sciences
Carlos Pilotto Heming, Wanjiru Muriithi, Lucy Wanjiku Macharia, Paulo Niemeyer Filho, Vivaldo Moura-Neto, Veronica Aran
Summary: Acquired resistance during cancer treatment is often caused by ABC transporters, such as P-gp, which export chemotherapeutic molecules and contribute to multidrug resistance. In addition to its role in drug resistance, P-gp may also have other functions and serve as a biomarker in cancer.
Review
Multidisciplinary Sciences
Iman Imtiyaz Ahmed Juvale, Azzmer Azzar Abdul Hamid, Khairul Bariyyah Abd Halim, Ahmad Tarmizi Che Has
Summary: The multidrug resistance phenomenon poses a significant threat to the pharmaceutical industry and is mediated by multidrug transporters like P-glycoprotein. P-glycoprotein, with its versatile binding sites, accommodates various compounds and plays crucial roles in both multidrug resistant diseases and physiological functions in the human body.
Review
Oncology
Jordan M. Hotz, Joanna R. Thomas, Emily N. Katz, Robert W. Robey, Sachi Horibata, Michael M. Gottesman
Summary: The blood-brain barrier is a network of specialized cells that protect the brain from toxins, allowing only essential molecules to enter. It employs various mechanisms to prevent harmful substances from entering, such as tight junctions and energy-dependent transporters like ABC transporters. Research on ABC transporters in zebrafish is ongoing to understand their role in the BBB and their potential as a model system for further study.
CANCER DRUG RESISTANCE
(2021)
Article
Biochemistry & Molecular Biology
Jae Pyun, Lachlan E. McInnes, Paul S. Donnelly, Celeste Mawal, Ashley Bush, Jennifer L. Short, Joseph A. Nicolazzo
Summary: The study found that copper II (ATSM) and copper II (GTSM) were able to modulate the expression and function of P-gp at the blood-brain barrier. Copper II (ATSM) significantly enhanced the expression and function of P-gp, while copper II (GTSM) reduced the expression and function of P-gp. This has important implications for brain drug delivery and clearance of Aβ.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Kiyotaka Daikohara, Shin-ichi Akanuma, Yoshiyuki Kubo, Ken-ichi Hosoya
Summary: This study investigated the alterations in P-gp activity at the inner blood-retinal barrier (BRB) caused by the inflammatory agent lipopolysaccharide (LPS) and the molecular mechanisms involved. The results showed that LPS reduced P-gp activity at the inner BRB, and this decrease was mediated by toll-like receptor 4 (TLR4) and protein kinase C (PKC) pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Sepehr Dehghani-Ghahnaviyeh, Karan Kapoor, Emad Tajkhorshid
Summary: This study used molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in Pgp nucleotide-binding domains (NBDs), revealing that ATP/ADP exchange induced conformational changes within the conserved signature motif of NBDs, resulting in relative orientational changes. Furthermore, putative hydrolysis-competent configurations were captured, with a conserved glutamate in the Walker-B motif acting as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.
Article
Chemistry, Multidisciplinary
Lara Garcia-Varela, Pascalle Mossel, Pablo Aguiar, Daniel A. Vazquez-Matias, Aren van Waarde, Antoon T. M. Willemsen, Anna L. Bartels, Nicola A. Colabufo, Rudi A. J. O. Dierckx, Philip H. Elsinga, Gert Luurtsema
Summary: This study found that small changes in P-gp function caused by low doses of tariquidar could be detected by [F-18]MC225-K-1 values, confirming the high sensitivity of the radiotracer.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Biochemistry & Molecular Biology
Anne Cloe Voirin, Morgane Chatard, Anne Briancon-Marjollet, Jean Louis Pepin, Nathalie Perek, Frederic Roche
Summary: Several sleep-related breathing disorders can lead to neurological diseases, such as cognitive impairment, due to repeated hypoxia stresses. However, the consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are not well recognized. This study compared two methods of intermittent hypoxia induction and found that both hydralazine and intermittent physical hypoxia progressively altered BBB integrity, with an increase in Na-Fl permeability and a decrease in tight junction protein concentration. The study also observed an adaptation of the BBB after the third cycle of intermittent hypoxia exposure.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Multidisciplinary
Nazneen Pathan, Pravin Shende
Summary: P-Glycoprotein plays a vital role in the blood-brain barrier, protecting the central nervous system from infections and external toxic molecules. It is essential in various brain-related conditions but also poses a significant challenge in drug delivery across the blood-brain barrier.
JOURNAL OF CONTROLLED RELEASE
(2021)
Article
Pharmacology & Pharmacy
Mengyue Yin, Flavia Storelli, Jashvant D. Unadkat
Summary: The study suggests that the protein-mediated uptake effect on OATP-transported drugs may be an artifact of the non-specific binding of the drug-albumin complex to cells/labware, highlighting the importance of considering such non-specific binding in future experiments on PMUE. Additionally, alternative mechanisms need to be explored to explain the underprediction of in vivo OATP-mediated hepatic drug clearance from in vitro uptake studies.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Aditya R. Kumar, Gabriela Patilea-Vrana, Olena Anoshchenko, Jashvant D. Unadkat
Summary: This study characterized and quantified the depletion clearance of (-)-Delta(9)-Tetrahydrocannabinol (THC) and (+/-)-11-hydroxy-Delta(9)-THC (11-OH-THC) by cytochrome P450 and UDP-glucuronosyltransferase enzymes in extrahepatic human tissues including the intestine, fetal liver, lung, and placenta. The data obtained can be used in physiologically based pharmacokinetic modeling and simulation to predict systemic and tissue exposure to THC/11-OH-THC after oral and inhalational use of THC in both healthy individuals and special populations such as pregnant women.
DRUG METABOLISM AND DISPOSITION
(2022)
Article
Pharmacology & Pharmacy
Mayur K. Ladumor, Jashvant D. Unadkat
Summary: The study developed an OI-PBPK model to predict the concentration of orally inhaled drugs in respiratory tissue and systemic circulation. The model was validated by comparing simulated and observed data and sensitivity analyses were performed to assess key parameters' impact.
DRUG METABOLISM AND DISPOSITION
(2022)
Editorial Material
Clinical Neurology
Sara Eyal
Summary: In an observational study of 28 children with drug-resistant epilepsy treated with the ketogenic diet, changes in gut microbiota and inflammation were identified during treatment. The findings suggest a general anti-inflammatory effect of KD, and specific Bifidobacteria and TNF may be associated with the efficacy of KD.
Editorial Material
Clinical Neurology
Roaa Hamed, Amit David Eyal, Erez Berman, Sara Eyal
Article
Pharmacology & Pharmacy
Sumit Bansal, C. Austin Zamarripa, Tory R. Spindle, Elise M. Weerts, Kenneth E. Thummel, Ryan Vandrey, Mary F. Paine, Jashvant D. Unadkat
Summary: Understanding the interactions between cannabis and drugs is crucial in light of increased access and use of cannabis due to regulatory changes. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are potent inhibitors of certain cytochrome P450 (CYP) enzymes. In this study, the potential pharmacokinetic interactions between cannabis extracts and common drugs were evaluated in healthy adults. The results showed that the CBD + Δ9-THC brownie significantly inhibited the activity of CYP2C19, CYP2C9, CYP3A, and CYP1A2 enzymes, while the Δ9-THC brownie did not inhibit any CYP enzymes. The findings can guide dose adjustments of drugs co-administered with cannabis products to minimize the risk of interactions with Δ9-THC.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Sumit Bansal, Mayur K. Ladumor, Mary F. Paine, Jashvant D. Unadkat
Summary: CBD is used as a prescription drug for treating epilepsy and as an over-the-counter product for various ailments. Predicting CBD-drug interactions can be done through PBPK modeling, using CBD-specific parameters and enzymes responsible for CBD metabolism. The developed PBPK model successfully predicts CBD systemic exposure in different populations, providing guidance for safe medication use.
DRUG METABOLISM AND DISPOSITION
(2023)
Review
Clinical Neurology
Firas Fahoum, Sara Eyal
Summary: Intracerebroventricular (ICV) administration is explored as a means to deliver antiseizure and antiepileptic therapies to epileptic brain tissue. This route bypasses the blood-brain barrier, allowing restricted therapeutics to reach the brain while reducing systemic adverse reactions. However, efficacy may be limited when epileptogenic tissue is far from the ventricles. This article provides an overview of ICV delivery and its challenges, and compares it with other administration routes.
Editorial Material
Clinical Neurology
Sara Eyal
Summary: In this study, the researchers found that activating channelrhodopsin-2-expressing astrocytes effectively reduces neocortical seizures in rodent models. This anti-seizure effect is independent of classical calcium signaling and is instead related to the astrocytic Na+K+-ATPase-mediated buffering K+, which inhibits firing in highly active pyramidal neurons during seizures. Compared to inhibiting pyramidal neurons, stimulating astrocytes has several advantages as an anti-seizure strategy, including a wider therapeutic window, greater efficacy, and minimal side effects. Furthermore, optogenetic-driven astrocytic Na+K+-ATPase shows promising therapeutic effects in a chronic focal cortical dysplasia epilepsy model.
Article
Pharmacology & Pharmacy
Mengyue Yin, Kazuya Ishida, Xiaomin Liang, Yurong Lai, Jashvant D. Unadkat
Summary: The inclusion of plasma in human hepatocyte uptake studies can reduce the gap in the extrapolation of organic anion transporting polypeptide (OATP)-mediated hepatic clearance (CLh) of statins from in vitro to in vivo. The protein-mediated uptake effect (PMUE) of statins previously observed in the presence of 5% human serum albumin (HSA) by OATP1B1-expressing cells is actually caused by residual statin-HSA complex in the uptake assay. This study disproves the prevailing hypotheses for the in vitro PMUE and suggests that the artifact can be reduced by using suspended human hepatocytes and the oil-spin method.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Clinical Neurology
Erez Berman, Natalia Erenburg, Ron Beloosesky, Sara Eyal, Michal Kovo
Summary: The study found that CBD is sequestered in placental tissue, with lower concentrations in the fetal compartment. CBD did not significantly alter placental gene expression. While the placenta acts as a depot for CBD, there are still potential risks associated with its use during pregnancy.
Article
Clinical Neurology
Adili Tsur, Ronen Spierer, Renana Cohen, Dana Blatch, Sara Eyal, Asaf Honig, Dana Ekstein
Summary: The incidence rate of first unprovoked seizures (FUS) is higher in combat soldiers, but they have a two-fold lower risk of additional seizures compared to noncombat soldiers. This highlights the value of strenuous triggers as negative predictors for developing epilepsy and suggests a shift in the perception of epilepsy, calling for changes in the weighting of epilepsy etiologies and delivery of treatments.
Editorial Material
Clinical Neurology
Sara Eyal
Summary: Cerebral hypoperfusion, which is characterized by decreased cerebral blood flow (CBF), is proposed as a potential cause of postictal neurological dysfunction in epilepsy. The study shows that a 30% reduction in postictal CBF has two contributing factors. The early hypoperfusion is mainly induced by arteriolar constriction, while the prolonged hypoperfusion is due to neutrophil adhesion to brain capillaries, decreased red blood cell flow, capillary and venule constriction, and elevated ICAM-1 expression. Antibodies against neutrophil marker Ly6G and against LFA-1 can prevent neutrophil adhesion and recover CBF reductions to control levels.
Article
Pharmacology & Pharmacy
Flavia Storelli, Mayur K. Ladumor, Xiaomin Liang, Yurong Lai, Paresh P. Chothe, Osatohanmwen J. Enogieru, Raymond Evers, Jashvant D. Unadkat
Summary: Hepatic impairment (HI) has different effects on the systemic exposure of drugs that are substrates of hepatic transporters. The impact of HI on drugs that are also substrates of cytochrome P450 enzymes is greater. Simulations using the extended clearance model showed that the ratio of sinusoidal efflux clearance (CL) to metabolic and biliary CLs is important in predicting the impact of HI on drug exposure. Physiologically-based pharmacokinetic modeling and simulation accurately predicted the drug exposure of OATP substrates, but underestimated the exposure of dual OATP/CYP3A4 substrates. Accurately predicting all hepatobiliary pathways, including sinusoidal efflux CL, is crucial for accurately predicting the effect of HI on AUC of hepatobiliary cleared drugs.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Mengyue Yin, Ankit Balhara, Solene Marie, Nicolas Tournier, Zsuzsanna Gaborik, Jashvant D. Unadkat
Summary: Tissue drug concentrations play a crucial role in determining drug efficacy and toxicity. The use of transporters for drug entry and exit at the blood:tissue barrier complicates the prediction of steady-state unbound tissue drug concentrations from corresponding plasma concentrations. To accurately predict transporter-modulated tissue drug concentrations, the authors propose the use of transporter-expressing cells/vesicles (TECs/TEVs) and relative expression factor (REF). The REF represents the abundance of relevant transporters in tissue compared to TECs/TEVs. By applying this approach, the authors successfully predicted transporter-based intrinsic clearance (CL) of glyburide (GLB) and pitavastatin (PTV) and scaled the CLs to in vivo conditions. The predictions for hepatic concentrations and clearances were within a twofold range of the observed data, confirming the potential of the REF approach in drug development.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2023)