Uptake Transporters at the Blood-Brain Barrier and Their Role in Brain Drug Disposition.

Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to preclinical to clinical translation. These transporters are members of the solute carrier (SLC) superfamily, which includes organic anion transporter polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), and amino acid transporters. In this systematic review, we provide an overview of the current knowledge of uptake drug transporters in the brain and their contribution to drug disposition. Here, we also assemble currently available proteomics-based expression levels of uptake transporters in the human brain and their application in translational drug development. Proteomics data suggest that in association with efflux transporters, uptake drug transporters present at the BBB play a significant role in brain drug disposition. It is noteworthy that a significant level of species differences in uptake drug transporters activity exists, and this may contribute toward a disconnect in inter-species scaling. Taken together, uptake drug transporters at the BBB could play a significant role in pharmacokinetics (PK) and pharmacodynamics (PD). Continuous research is crucial for advancing our understanding of active uptake across the BBB.

A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation.

Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen's effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3,9 = 6.03, p = 0.01; alcohol sedation: F3,6 = 7.16, p = 0.01) on the total amount of alcohol self-administered. Considerable interindividual variability in baclofen pharmacokinetic parameters was observed. Maximum plasma concentrations of baclofen negatively correlated with cue-induced alcohol craving (r = -0.57, p = 0.03) and priming-induced ratings of 'like more' (r = -0.59, p = 0.02). In conclusion, baclofen may work by dissociating the link between an initial drink (priming) and subsequent alcohol consumption (self-administration). Considerable pharmacokinetic variability is an important factor to take into account when employing baclofen as a treatment for alcohol use disorder.

Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs.

AIMS: A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. METHODS: A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. RESULTS: Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). CONCLUSIONS: The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016.

BACKGROUND: Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved). OBJECTIVE: Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance. METHODS: The University of Washington Drug Interaction Database (DIDB®) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends. RESULTS: Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å2) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively. CONCLUSIONS: The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.

Magnetic bio-metal-organic framework nanocomposites decorated with folic acid conjugated chitosan as a promising biocompatible targeted theranostic system for cancer treatment.

In this work, a multifunctional magnetic Bio-Metal-Organic Framework (Fe3O4@Bio-MOF) coated with folic acid-chitosan conjugate (FC) was successfully prepared for tumor-targeted delivery of curcumin (CUR) and 5-fluorouracil (5-FU) simultaneously. Bio-MOF nanocomposite based on CUR as organic linker and zinc as metal ion was prepared by hydrothermal method in the presence of amine-functionalized Fe3O4 magnetic nanoparticles (Fe3O4@NH2 MNPs). 5-FU was loaded in the magnetic Bio-MOF and the obtained nanocarrier was then coated with FC network. The prepared nanocomposite (NC) was fully characterized by high resolution-transmission electron microscope (HR-TEM), field emission scanning electron microscopy (FE-SEM), Dynamic light scattering (DLS), X-ray diffraction analysis (XRD), thermogravimetric analysis (TGA), vibrating sample magnetometry (VSM), nuclear magnetic resonance (NMR), and UV-vis analyses. In vitro release study showed controlled release of CUR and 5-FU in acidic pH confirming high selectivity and performance of the carrier in cancerous microenvironments. The selective uptake of 5-FU-loaded Fe3O4@Bio-MOF-FC by folate receptor-positive MDA-MB-231 cells was investigated and verified. The ultimate nanocarrier exhibited no significant toxicity, while drug loaded nanocarrier showed selective and higher toxicity against the cancerous cells than normal cells. SDS PAGE was also utilized to determine the protein pattern attached on the surface of the nanocarriers. In vitro and in vivo MRI studies showed negative signal enhancement in tumor confirming the ability of the nanocarrier to be applied as diagnostic agent. Owing to the selective anticancer release and cellular uptake, acceptable blood compatibility as well as suitable T2 MRI contrast performance, the target nanocarrier could be considered as favorable theranostic in breast cancer.

Gold-capped mesoporous silica nanoparticles as an excellent enzyme-responsive nanocarrier for controlled doxorubicin delivery.

Mesoporous silica nanoparticles (MSNs) have ideal characteristics as next generation of controlled drug delivery systems. In this study, a MSN-based nanocarrier was fabricated and gold nanoparticle (GNP)-biotin conjugates were successfully grafted onto the pore outlets of the prepared MSN. This bioconjugate served as a capping agent with a peptide-cleavable linker sensitive to matrix metalloproteinases (MMPs), which are overexpressed extracellular proteolytic enzymes in cancerous tissue. The prepared nanocarriers were fully characterised by scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption/desorption, Fourier transform infra-red spectroscopy (FTIR), dynamic light scattering (DLS) and thermo gravimetric analysis (TGA). In vitro release studies showed efficient capping of MSNs with gold gate and controlled release of Doxorubicin (DOX) in the presence of matrix metalloproteinase-2 (MMP-2) and acidic pH values. High DOX-loading capacity (21%) and encapsulation efficiency (95.5%) were achieved using fluorescence technique. DOX-loaded nanocarriers showed high cytocompatibility and could efficiently induce cell death and apoptosis in the MMP-2 overexpressed cell lines. Moreover, Haemolysis, platelet activation and inflammatory responses assessment approved excellent hemocompatibility and minimal side effects by encapsulation of DOX in MSNs carrier.

Poly(Acrolein-co-ß-Cyclodextrin) Functionalized Magnetic Nanoparticles for Selective CD45-Positive Cells Capturing.

In this work, a new magnetic nanocomposite was prepared for the specific isolation of CD45 positive cells. Acrolein (AC) and acrylated ß-cyclodextrin (ACD) were used as monomers in order to polymerize on the surface of Fe3O4 magnetic nanoparticles (MNPs) via surface initiated radical polymerization. Polyacrolein-ß-CD (PACD) functionalized Fe3O4 MNPs (Fe3O4@PACD) was achieved and subsequently, fluorescein conjugated IgG anti-human CD45 was immobilized onto Fe3O4@PACD. Antibody conjugation onto the latter nanocomposite was accomplished according to IgG encapsulation in cyclodextrin cavity and Schiff base formation between aldehyde groups of MNPs and primary amines of antibody. The characterization analysis of the bare Fe3O4, Fe3O4@PACD nanocomposite, and Fe3O4@PACD-Ab were investigated using XRD, VSM, FT-IR, H-NMR, TGA, SEM, TEM, and flow cytometry techniques. The results showed that the antibody has been successfully immobilized onto Fe3O4@PACD. Moreover, the fabricated nanocomposite was used for selective capturing of CD45+ cells among other peripheral blood mononuclear cells (PBMCs). The results of TEM and fluorescence microscopy confirmed the ability of the conjugated system for efficient cell capturing.

Metal-Chelate Immobilization of Lipase onto Polyethylenimine Coated MCM-41 for Apple Flavor Synthesis.

An enzyme immobilized on a mesoporous silica nanoparticle can serve as a multiple catalyst for the synthesis of industrially useful chemicals. In this work, MCM-41 nanoparticles were coated with polyethylenimine (MCM-41@PEI) and further modified by chelation of divalent metal ions (M = Co2+, Cu2+, or Pd2+) to produce metal-chelated silica nanoparticles (MCM-41@PEI-M). Thermomyces lanuginosa lipase (TLL) was immobilized onto MCM-41, MCM-41@PEI, and MCM-41@PEI-M by physical adsorption. Maximum immobilization yield and efficiency of 75 ± 3.5 and 65 ± 2.7% were obtained for MCM@PEI-Co, respectively. The highest biocatalytic activity at extremely acidic and basic pH (pH = 3 and 10) values were achieved for MCM-PEI-Co and MCM-PEI-Cu, respectively. Optimum enzymatic activity was observed for MCM-41@PEI-Co at 75 °C, while immobilized lipase on the Co-chelated support retained 70% of its initial activity after 14 days of storage at room temperature. Due to its efficient catalytic performance, MCM-41@PEI-Co was selected for the synthesis of ethyl valerate in the presence of valeric acid and ethanol. The enzymatic esterification yield for immobilized lipase onto MCM-41@PEI-Co was 60 and 53%, respectively, after 24 h of incubation in n-hexane and dimethyl sulfoxide media. Graphical Abstract Divalent metal chelated polyethylenimine coated MCM-41 (MCM-41@PEI-M) was used for immobilization of Thermomyces lanuginosa lipase catalyzing green apple flavor preparation.

Immobilisation of lipase on the surface of magnetic nanoparticles and non-porous glass beads for regioselective acetylation of prednisolone.

Magnetic nanoparticles (MNPs) were prepared by co-precipitation of Fe+3/Fe+2 (2:1; molar ratio) with a mean size of 40 ± 5 nm. Scanning electron microscopy, dynamic light scattering, X-ray diffraction, vibrating sample magnetometer and thermogravimetric analysis were used to characterise the MNPs. The MNPs and also hydroxylated nonporous glass beads were similarly functionalised with the aid of glutaraldehyde to be cross-linked to lipase originated from Thermomyces lanuginosus (TLL). The yield and efficiency for immobilised lipase on the MNPs were calculated as 72 ± 2.4 and 63 ± 3.5%, whereas a yield and efficiency of 60 ± 2.1 and 55 ± 4.1%, respectively, were measured for the corresponding parameters of the immobilised enzyme on the glass beads. When the immobilised TLL was compared with its free form, Michaelis-Menten kinetics indicated an insignificant change in the Michaelis constant (Km) and a drastic decrease in the maximum substrate conversion rate (Vmax). The immobilised TLL and six other commercial lipases were then checked for regioselective acetylation of prednisolone. The highest and lowest yields of the product were observed for Novozym 435 and immobilised TLL on the glass beads, respectively. Immobilised TLL retained its bioacetylation activity of prednisolone in five successive catalytic processes.

Insights into biogenic and chemical production of inorganic nanomaterials and nanostructures.

The synthesis of inorganic nanomaterials and nanostructures by the means of diverse physical, chemical, and biological principles has been developed in recent decades. The nanoscale materials and structures creation continue to be an active area of researches due to the exciting properties of the resulting nanomaterials and their innovative applications. Despite physical and chemical approaches which have been used for a long time to produce nanomaterials, biological resources as green candidates that can replace old production methods have been focused in recent years to generate various inorganic nanoparticles (NPs) or other nanoscale structures. Cost-effective, eco-friendly, energy efficient, and nontoxic produced nanomaterials using diverse biological entities have been received increasing attention in the last two decades in contrast to physical and chemical methods owe using toxic solvents, generate unwanted by-products, and high energy consumption which restrict the popularity of these ways employed in nanometric science and engineering. In this review, the biosynthesis of gold, silver, gold-silver alloy, magnetic, semiconductor nanocrystals, silica, zirconia, titania, palladium, bismuth, selenium, antimony sulfide, and platinum NPs, using bacteria, actinomycetes, fungi, yeasts, plant extracts and also informational bio-macromolecules including proteins, polypeptides, DNA, and RNA have been reported extensively to mention the current status of the biological inorganic nanomaterial production. In other hand, two well-known wet chemical techniques, namely chemical reduction and sol-gel methods, used to produce various types of nanocrystalline powders, metal oxides, and hybrid organic-inorganic nanomaterials have presented.

Removal of chlorophenolic derivatives by soil isolated ascomycete of Paraconiothyrium variabile and studying the role of its extracellular laccase.

The ability of Paraconiothyrium variabile, a laccase producing ascomycete recently isolated from soil, was studied to eliminate chlorophenol derivatives in submerged culture medium. Among the tested compounds, ρ-chlorophenol (ρ-CP) and pentachlorophenol (PCP) were found to have minimum and maximum toxic effects, respectively, on the growth of the microorganism and at the same time high and low bioelimination percentages. The fungal strain was able to remove 86% of ρ-CP (with initial concentration of 40 mg l(-1)) and 56% of 2,4-dichlorophenol (2,4-DCP; with same concentration as ρ-CP) after 9 days of incubation while no elimination was observed in the presence of 2,4,6-trichlorophenol (2,4,6-TCP) and PCP. Monitoring of laccase production level in the fermentation broth together with pollutant removal confirmed the key role of this copper-containing oxidase in chlorophenol derivatives elimination. The type of laccase inducer (guaiacol) and its final concentration (250 µM) and also initial pH of the fermentation broth (pH=5.5) in the elimination of ρ-CP increased the final removal yield from 86% to 94.3%.

Mathematical modelling of the transport of hydroxypropyl-ß-cyclodextrin inclusion complexes of ranitidine hydrochloride and furosemide loaded chitosan nanoparticles across a Caco-2 cell monolayer.

Chitosan nanoparticles (CS-NPs) have been used to enhance the permeability of furosemide and ranitidine hydrochloride (ranitidine HCl) which were selected as candidates for two different biopharmaceutical drug classes having low permeability across Caco-2 cell monolayers. Drugs loaded CS-NPs were prepared by ionic gelation of CS and pentasodium tripolyphosphate (TPP) which added to the drugs inclusion complexes with hydroxypropyl-ß-cyclodextrin (HP-ßCD). The stability constants for furosemide/HP-ßCD and ranitidine HCl/HP-ßCD were calculated as 335 M(-1) and 410 M(-1), whereas the association efficiencies (AE%) of the drugs/HP-ßCD inclusion complexes with CS-NPs were determined to be 23.0 and 19.5%, respectively. Zetasizer and scanning electron microscopy (SEM) were used to characterise drugs/HP-ßCD-NPs size and morphology. Transport of both nano and non-nano formulations of drugs/HP-ßCD complexes across a Caco-2 cell monolayer was assessed and fitted to mathematical models. Furosemide/HP-ßCD-NPs demonstrated transport kinetics best suited for the Higuchi model, whereas other drug formulations demonstrated power law transportation behaviour. Permeability experiments revealed that furosemide/HP-ßCD and ranitidine HCl/HP-ßCD nano formulations greatly induce the opening of tight junctions and enhance drug transition through Caco-2 monolayers.