The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the majority of membrane drug transport processes in biological systems. Based on evidence of the physicochemical characteristics and of in vitro and in vivo findings for marketed drugs, as well as results from real-life discovery and development projects, we present the view that both passive transcellular processes and carrier-mediated processes coexist and contribute to drug transport activities across biological membranes.

Coexistence of passive and carrier-mediated processes in drug transport

Role of nanoparticle size, shape and surface chemistry in oral drug delivery.

ObjectiveThousands of chemicals are in common use, but only a portion of them have undergone significant toxicologic evaluation, leading to the need to prioritize the remainder for targeted testing...

The Toxicity Data Landscape for Environmental Chemicals

Potential drug-drug interactions mediated by the ATP-binding cassette (ABC) transporter and solute carrier (SLC) transporter families are of clinical and regulatory concern. However, the endogenous functions of these drug transporters are not well understood. Discussed here is evidence for the roles of ABC and SLC transporters in the handling of diverse substrates, including metabolites, antioxidants, signalling molecules, hormones, nutrients and neurotransmitters. It is suggested that these transporters may be part of a larger system of remote communication ('remote sensing and signalling') between cells, organs, body fluid compartments and perhaps even separate organisms. This broader view may help to clarify disease mechanisms, drug-metabolite interactions and drug effects relevant to diabetes, chronic kidney disease, metabolic syndrome, hypertension, gout, liver disease, neuropsychiatric disorders, inflammatory syndromes and organ injury, as well as prenatal and postnatal development.

/pdf/what-do-drug-transporters-really-do-38qhzmz4ln.pdf

What do drug transporters really do

Graphene and its derivatives are heralded as ‘miracle’ materials with manifold applications in different sectors of society from electronics to energy storage to medicine. The increasing exploitation of graphene-based materials (GBMs) necessitates a comprehensive evaluation of the potential impact of these materials on human health and the environment. Here we discuss synthesis and characterization of GBMs as well as human and environmental hazard assessment of GBMs using in vitro and in vivo model systems with the aim to understand the properties that underlie the biological effects of these materials; not all GBMs are alike, and it is essential that we disentangle the structure-activity relationships for this class of materials.

/pdf/safety-assessment-of-graphene-based-materials-focus-on-human-5cvsuf4q4q.pdf

Safety assessment of graphene-based materials: focus on human health and the environment

Background: The Caco-2 monolayer has been used extensively for the high-throughput screening of drug permeability and identification of substrates, inhibitors, and inducers of intestinal transporters, especially P-glycoprotein (P-gp). Traditionally, the Caco-2 monolayer is viewed as a single barrier rather than a polarized cell monolayer consisting of metabolic enzymes that are sandwiched between two membrane barriers with distinctly different transporters. Objective: This review addressed the usefulness and limitations of the Caco-2 cell monolayer in drug discovery and mechanistic studies. Methods: This mini-review covered applications of the Caco-2 monolayer, clarified misconceptions, and critically addressed issues on data interpretation. Conclusion: The catenary model extends the usefulness of Caco-2 monolayer and provides proper mechanistic insight and data interpretation.

The Caco-2 cell monolayer: usefulness and limitations

We explored the properties of a catenary model that includes the basolateral (B), apical (A), and cellular compartments via simulations under linear and nonlinear conditions to understand the asymmetric observations arising from transporters, enzymes, and permeability in Caco-2 cells The efflux ratio (EfR; Papp,B→A/Papp,A→B), obtained from the effective permeability from the A→B and B→A direction under linear conditions, was unity for passively permeable drugs whose transport does not involve transporters; the value was unaffected by cellular binding or metabolism, but increased with apical efflux Metabolism was asymmetric, showing lesser metabolite accrual for the B→A than A→B direction because of inherent differences in the volumes for A and B Moreover, the net flux (total - passive permeation) due to saturable apical efflux, absorption, or metabolism showed nonconformity to simple Michaelis-Menten kinetics against CD,0, the loading donor concentration EfR values differed with saturable apical efflux and metabolism (>1), as well as apical absorption (EfRs

https://dmd.aspetjournals.org/content/dmd/early/2007/10/11/dmd.107.015321.full.pdf

Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study

1 alpha,25-Dihydroxyvitamin D-3 (1,25(OH)(2)D-3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)(2)D-3 treatment (0 to 2.56 nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)(2)D-3 treatment. In the kidney, VDR, Cyp24, Asbt and Mdr1a mRNA and protein expression increased significantly (2- to 20-fold) in 1,25(OH)(2)D-3-treated rats, and a 28-fold increase of Cyp3a9 mRNA but not of total Cy3a protein nor Cyp3a1 and Cyp3a2 mRNA was observed, implicating that VDR played a significant, renal-specific role in Cyp3a9 induction. Additionally, renal mRNA levels of PepT1, Oat1, Oat3, Ost alpha, and Mrp4, and protein levels of PepT1 and Oatl were decreased in a dose-dependent manner, and the similar to 50% concomitant reduction in FXR, SHP, HNF-1 alpha and HNF-4 alpha mRNA expression suggests the possibility of cross-talk among the nuclear receptors. It is concluded that the effects of 1,25(OH)(2)D-3 changes are tissue-specific, differing between the intestine and kidney which are VDR-rich organs. Copyright (C) 2009 John Wiley & Sons, Ltd.

Effects of 1 alpha,25-Dihydroxyvitamin D-3 on Transporters and Enzymes of the Rat Intestine and Kidney In Vivo

The administration of metabolites arising from new drug entities is often employed in drug discovery to investigate their associated toxicity. It is expected that administration of metabolites can predict the exposure of metabolites originating from the administration of precursor drug. Whether exact and meaningful information can be obtained from this has been a topic of debate. This communication summarizes observations and theoretical relationships based on physiological modelling for the liver, kidney and intestine, three major eliminating organs/tissues. Theoretical solutions based on physiological modelling of organs were solved, and the results suggest that deviations are expected. Here, examples of metabolite kinetics observed mostly in perfused organs that did not match predictions are provided. For the liver, discrepancies in fate between formed and preformed metabolites may be explained by the heterogeneity of enzymes, the presence of membrane barriers and whether transporters are involved. For the kidney, differences have been attributed to glomerular filtration of the preformed but not the formed metabolite. For the intestine, the complexity of segregated flows to the enterocyte and serosal layers and differences in metabolism due to the route of administration are addressed. Administration of the metabolite may or may not directly reflect the toxicity associated with drug use. However, kinetic data on the preformed metabolite will be extremely useful to develop a sound model for modelling and simulations; in-vitro evidence on metabolite handling at the target organ is also paramount. Subsequent modelling and simulation of metabolite data arising from a combined model based on both drug and preformed metabolite data are needed to improve predictions on the behaviours of formed metabolites.

Formed and preformed metabolites: facts and comparisons

We thank Dr Yuan-Sheng Zhao for the interest and comments regarding our published article ([Sun and Pang, 2008][1]) In the Letter to the Editor “Comment on Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study” Drug Metab Dispos 534, Zhao suggested

Huadong Sun

Papers

The Caco-2 cell monolayer: usefulness and limitations

Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study

Effects of 1 alpha,25-Dihydroxyvitamin D-3 on Transporters and Enzymes of the Rat Intestine and Kidney In Vivo

Formed and preformed metabolites: facts and comparisons

Response to Letter to the Editor on “Permeability, Transport, and Metabolism of Solutes in Caco-2 Cell Monolayers: A Theoretical Study”