The Interplay between Liver First-Pass Effect and Lymphatic Absorption of Cannabidiol and its Implications for Cannabidiol Oral Formulations

For highly lipophilic drugs, passage into the intestinal lymphatic system rather than the portal vein following oral administration may represent a major alternative route of delivery into the general circulation. Increasing intestinal lymphatic transport provides an effective strategy to improve oral bioavailability when hepatic first-pass metabolism is a major rate-limiting step hampering access to the systemic circulation after oral dosing. The transfer of orally administered, highly lipid-soluble drugs to the lymphatic system is mediated by their association with chylomicrons, large intestinal lipoproteins that are assembled in the enterocytes in the presence of long-chain triglycerides or long-chain fatty acids. Due to its very high lipophilicity, cannabidiol (CBD) has physicochemical features (e.g. logP = 6.3) consistent with an oral absorption mediated at least in part by transport via the intestinal lymphatic system. CBD also undergoes extensive first-pass hepatic metabolism. Formulation changes favoring diversion of orally absorbed CBD from the portal to the lymphatic circulation pathway can result in reduced first-pass liver metabolism, enhanced oral bioavailability, and reduced intra- and intersubject variability in systemic exposure. In this manuscript, we discuss (1) evidence for CBD undergoing hepatic first-pass liver metabolism and lymphatic absorption to a clinically important extent; (2) the potential interplay between improved oral absorption, diversion of orally absorbed drug to the lymphatic system, and magnitude of presystemic elimination in the liver; and (3) strategies by which innovative chemical and/or pharmaceutical delivery systems of CBD with improved bioavailability could be developed

Predicting intestinal and hepatic first-pass metabolism of orally administered testosterone 3 undecanoate 4

The bioavailability of orally administered drugs could be impacted by intestinal and 12 hepatic first-pass metabolism. Testosterone undecanoate (TU), an orally administered ester prodrug 13 of testosterone, is significantly subjected to first-pass metabolism. Yet, the individual contribution 14 of intestinal and hepatic first-pass metabolism is not well determined. Therefore, the aim of the 15 current study was to predict the contribution of each site. The hydrolysis-time profiles of TU 16 incubation in human liver microsomes and Caco-2 cell homogenate were used to predict hepatic 17 and intestinal first-pass metabolism, respectively. The in vitro half-life (t1/2 inv) for the hydrolysis of 18 TU in microsomal mixtures was 28.31 ± 3.51 min. By applying the "well-stirred" model, the fraction 19 of TU that could escape hepatic first-pass metabolism (FH) was predicted as 0.915 ± 0.009. The 20 incubation of TU in Caco-2 cell homogenate yielded t1/2 inv of 109.28 ± 21.42 min which was applied 21 in "Q gut" model to estimate the fraction of TU that would escape intestinal first-pass metabolism 22 (FG) as 0.114 ± 0.02. Accordingly, only 11% of the absorbed fraction of TU could escape intestinal 23 metabolism while 91% of which can pass hepatic metabolism. Hence, compared to the liver, the 24 intestinal wall is the main site where TU is significantly metabolised during first-pass effect. 2

Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer

We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.4) but rapidly cleaved at higher pH (pH 7.4). Compound (19), which was designed for optimal lung retention, demonstrated clean liberation of the drug payloads in vitro and represents a novel approach to targeted lung delivery

In vitro anticancer properties and biological evaluation of novel natural alkaloid jerantinine B

Natural products play a pivotal role in medicine especially in the cancer arena. Many drugs that are currently used in cancer chemotherapy originated from or were inspired by nature. Jerantinine B (JB) is one of seven novel Aspidosperma indole alkaloids isolated from the leaf extract of Tabernaemontana corymbosa. Preliminary antiproliferative assays revealed that JB and JB acetate significantly inhibited growth and colony formation, accompanied by time- and dose-dependent apoptosis induction in human cancer cell lines. JB significantly arrested cells at the G2/M cell cycle phase, potently inhibiting tubulin polymerisation. Polo-like kinase 1 (PLK1; an early trigger for the G2/M transition) was also dose-dependently inhibited by JB (IC50 1.5 µM). Furthermore, JB provoked significant increases in reactive oxygen species (ROS). Annexin V+ cell populations, dose-dependent accumulation of cleaved-PARP and caspase 3/7 activation, and reduced Bcl-2 and Mcl-1 expression confirm apoptosis induction. Preclinical in silico biopharmaceutical assessment of JB calculated rapid absorption and bioavailability >70%. Doses of 8–16 mg/kg JB were predicted to maintain unbound plasma concentrations >GI50 values in mice during efficacy studies. These findings advocate continued development of JB as a potential chemotherapeutic agent

Oral lipid-based formulations alter delivery of cannabidiol to different anatomical regions in the brain.

Delivery to the brain is a challenging task due to its protection by the blood-brain barrier (BBB). Lipids and fatty acids are reported to affect the permeability of the BBB, although this has not been reported following oral administration. Cannabidiol (CBD) has high therapeutic potential in the brain, therefore, tis work investigated CBD delivery to anatomical brain regions following oral administration in lipid-based and lipid-free vehicles. All formulations resulted in a short brain Tmax (1 h) and brain-plasma ratios ≥3.5, with retention up to 18 h post administration. The highest CBD delivery was observed in the olfactory bulb and striatum, and the medulla pons and cerebellum the lowest. The lipid-free vehicle led to the highest levels of CBD in the whole brain. However, when each anatomical region was assessed individually, the long chain triglyceride-rich rapeseed oil formulation commonly showed optimal performance. The medium chain triglyceride-rich coconut oil formulation did not result in the highest CBD concentration in any brain region. Overall, differences in CBD delivery to the whole brain and various brain regions were observed following administration in different formulations, indicating that the oral formulation selection may be important for optimal delivery to specific regions of the brain

Cannabidiol and fluorinated derivative anti-cancer properties against glioblastoma multiforme cell lines, and synergy with imidazotetrazine agents

BackgroundGlioblastoma multiforme (GBM) is an aggressive cancer with poor prognosis, partly due to resistance to the standard chemotherapy treatment, temozolomide (TMZ). Phytocannabinoid cannabidiol (CBD) has exhibited anti-cancer effects against GBM, however, CBD’s ability to overcome common resistance mechanisms to TMZ have not yet been investigated. 4’-Fluoro-cannabidiol (4’-F-CBD, or HUF-101/PECS-101) is a derivative of CBD, that exhibits increased activity compared to CBD during in vivo behavioural studies.MethodsThis anti-cancer activity of cannabinoids against GBM cells sensitive to and representing major resistance mechanisms to TMZ was investigated. Cannabinoids were also studied in combination with imidazotetrazine agents, and advanced mass spectrometry with the 3D OrbiSIMS was used to investigate the mechanism of action of CBD.ResultsCBD and 4’-F-CBD were found to overcome two major resistance mechanisms (methylguanine DNA-methyltransferase (MGMT) overexpression and DNA mismatch repair (MMR)-deficiency). Synergistic responses were observed when cells were exposed to cannabinoids and imidazotetrazine agents. Synergy increased with T25 and 4’-F-CBD. 3D OrbiSIMS analysis highlighted the presence of methylated-DNA, a previously unknown anti-cancer mechanism of action of CBD.ConclusionsThis work demonstrates the anti-cancer activity of 4’-F-CBD and the synergy of cannabinoids with imidazotetrazine agents for the first time and expands understanding of CBD mechanism of action

Use of Magnetic Resonance Imaging for Visualization of Oral Dosage Forms in the Human Stomach: A Scoping Review

Oral dosage forms are the most widely and frequently used formulations to deliver active pharmaceutical ingredients (APIs), due to their ease of administration and noninvasiveness. Knowledge of intragastric release rates and gastric mixing is crucial for predicting the API release profile, especially for immediate release formulations. However, knowledge of the intragastric fate of oral dosage forms in vivo to date is limited, particularly for dosage forms administered when the stomach is in the fed state. An improved understanding of gastric food processing, dosage form location, disintegration times, and food effects is essential for greater understanding for effective API formulation design. In vitro standard and controlled modeling has played a significant role in predicting the behavior of dosage forms in vivo. However, discrepancies are reported between in vitro and in vivo disintegration times, with these discrepancies being greatest in the fed state. Studying the fate of a dosage form in vivo is a challenging process, usually requiring the use of invasive methods, such as intubation. Noninvasive, whole body imaging techniques can however provide unique insights into this process. A scoping review was performed systematically to identify and critically appraise published studies using MRI to visualize oral solid dosage forms in vivo in healthy human subjects. The review identifies that so far, an all-purpose robust contrast agent or dosage form type has not been established for dosage form visualization and disintegration studies in the gastrointestinal system. Opportunities have been identified for future studies, with particular focus on characterizing dosage form disintegration for development after the consumption food, as exemplified by the standard Food and Drug Administration (FDA) high fat meal

Is oral lipid-based delivery for drug targeting to the brain feasible?

This review outlines the feasibility of oral lipid-based targeted delivery of drugs to the brain, including permeation of the central nervous system's (CNS) protective blood–brain barrier (BBB). The structure of the BBB and disruption caused by varying disease states highlights the need for disease-specific approaches to alter permeation. Disruption during disease state, and the effects of certain molecules on the barrier, demonstrate the possibility of exploiting such BBB disruption for drug delivery. Many administration methods can be used to target the brain, but oral administration is considered ideal for chronic, long-term illnesses. Several lipids that have been shown to facilitate drug delivery into the brain after systemic administration, but could also be delivered orally, are discussed, including oleic acid, triolein, alkylglycerol, and conjugates of linoleic and myristic acids. Current data reveal the potential for the use of such lipids as part of oral formulations for delivery to the brain by reaching sufficient plasma levels after administration to increase the permeability of the BBB. However, gaps in the literature remain regarding the concentrations and form of most lipids required to produce the desired effects. The use of lipids via oral delivery for brain targeting has not been investigated thoroughly enough to determine with certainty if similar permeability-enhancing effects would be observed as for parenteral administration. In conclusion, further research to fill research gaps is needed, but the limited evidence suggests that oral lipid-based drug delivery for brain targeting is potentially feasible