A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans.

Background: Cannabidiol is being pursued as a therapeutic treatment for multiple conditions, usually by oral delivery. Animal studies suggest oral bioavailability is low, but literature in humans is not sufficient. The aim of this review was to collate published data in this area. Methods: A systematic search of PubMed and EMBASE (including MEDLINE) was conducted to retrieve all articles reporting pharmacokinetic data of CBD in humans. Results: Of 792 articles retireved, 24 included pharmacokinetic parameters in humans. The half-life of cannabidiol was reported between 1.4 and 10.9 h after oromucosal spray, 2-5 days after chronic oral administration, 24 h after i.v., and 31 h after smoking. Bioavailability following smoking was 31% however no other studies attempted to report the absolute bioavailability of CBD following other routes in humans, despite i.v formulations being available. The area-under-the-curve and Cmax increase in dose-dependent manners and are reached quicker following smoking/inhalation compared to oral/oromucosal routes. Cmax is increased during fed states and in lipid formulations. Tmax is reached between 0 and 4 h. Conclusions: This review highlights the paucity in data and some discrepancy in the pharmacokinetics of cannabidiol, despite its widespread use in humans. Analysis and understanding of properties such as bioavailability and half-life is critical to future therapeutic success, and robust data from a variety of formulations is required.

New fluorescent adenosine A1-receptor agonists that allow quantification of ligand-receptor interactions in microdomains of single living cells.

Fluorescence spectroscopy is becoming a valuable addition to the array of techniques available for scrutinizing ligand-receptor interactions in biological systems. In particular, scanning confocal microscopy and fluorescence correlation spectroscopy (FCS) allow the noninvasive imaging and quantification of these interactions in single living cells. To address the emerging need for fluorescently labeled ligands to support these technologies, we have developed a series of red-emitting agonists for the human adenosine A1-receptor that, collectively, are N6-aminoalkyl derivatives of adenosine or adenosine 5'-N-ethyl carboxamide. The agonists, which incorporate the commercially available fluorophore BODIPY [630/650], retain potent and efficacious agonist activity, as demonstrated by their ability to inhibit cAMP accumulation in chinese hamster ovary cells expressing the human adenosine A1-receptor. Visualization and confirmation of ligand-receptor interactions at the cell membrane were accomplished using confocal microscopy, and their suitability for use in FCS was demonstrated by quantification of agonist binding in small areas of cell membrane.

Application of fluorescence correlation spectroscopy to the measurement of agonist binding to a G-protein coupled receptor at the single cell level.

The A1-adenosine receptor (A1-AR) is a member of the G-protein coupled receptor superfamily, which has significant pathophysiological importance in disorders such as heart arrhythmias, asthma and stroke. Here, we have used fluorescence correlation spectroscopy (FCS) to facilitate the study of A1-AR pharmacology at the subcellular level. To this end, we have successfully designed and synthesised a fluorescently labelled A1-AR agonist, ABA-BY630. ABA-BY630 is an N6- derivative of adenosine conjugated to the red-excited fluorophore, BODIPY" 630/650. In CHO cells expressing the human A1-AR, ABA-BY630 shows strong and potent agonist activity at this receptor. Specific binding of ABA-BY630 to the A1-AR in cell membranes of living CHO cells can also be visualised using confocal microscopy. Moreover, using FCS, we can detect and quantify the binding of ABA-BY630 to the A1-AR in a small area (0.2 microm2) of the upper cell membrane. FCS measurements indicate the presence of at least two populations of receptor-ABA-BY630 complexes with diffusion times of 8 and 233 ms. The quantity of both of these complexes was significantly reduced by pre-incubation with the A1-AR antagonist DPCPX. Application of FCS in conjunction with ABA-BY630 will allow the comparison of A1-AR pharmacology in single cells from healthy and diseased tissue.