Intestinal Lymph Flow, and Lipid and Drug Transport Scale Allometrically From Pre-clinical Species to Humans

Trevaskis, Natalie L.; Lee, Given; Escott, Alistair B.J.; Phang, Kian Liun; Hong, Jiwon; Cao, Enyuan; Katneni, Kasiram; Charman, Susan A.; Han, Sifei; Charman, William N.; Phillips, Anthony R. J.; Windsor, John A.; Porter, Christopher John

doi:10.3389/fphys.2020.00458

Cited by 29 publications

(17 citation statements)

References 47 publications

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“…With respect specifically to flymph, this is influenced primarily by a drug's ability to associate with chylomicrons in the enterocyte, which in turn is dependent on the drug's physicochemical properties, availability of a source of lipids (especially long-chain lipids) and characteristics of the formulation [25,32]. By stimulating the production of lymph, dietary or formulation-based lipids can also increase mesenteric lymphatic flow [41],…”

Section: The Interplay Between Cbd Oral Absorption Lymphatic Transport and Liver Firstpass Metabolismmentioning

confidence: 99%

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

et al. 2020

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 Cannabidiol (CBD) has low and variable oral bioavailability (approximately 6% on average), due to incomplete gastrointestinal absorption and extensive pre-systemic elimination in the liver. Because of its very high lipophilicity, CBD has physicochemical features (e.g. logP=6.3) consistent with absorption being mediated at least in part by transport via the intestinal lymphatic system. Innovative products/formulations that improve CBD solubilization in the gastrointestinal tract and re-route orally absorbed CBD from the portal to the lymphatic circulation can reduced the extent of hepatic first-pass metabolism, enhance oral bioavailability and reduce intra-and inter-subject variability in systemic exposure. The potential interplay between improved oral absorption, diversion of orally absorbed drug to the lymphatic system, and magnitude of hepatic-first pass effect should be considered in the design of new chemical and/or pharmaceutical delivery systems of CBD.

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Section: The Interplay Between Cbd Oral Absorption Lymphatic Transport and Liver Firstpass Metabolismmentioning

confidence: 99%

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

et al. 2020

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“…lymph flow rate increases in direct proportion to increases in body mass to the power of 0.9 (Trevaskis et al, 2020). Using the same calculations for allometric analysis (Trevaskis et al, 2020), the scaling exponent for cervical lymph flow rate from one side was 0.8 across species (rats, rabbits, cats and sheep). This suggests cervical lymph flow rate also increases in proportion to body weight across species and that studies conducted in several species may be able to predict cervical lymph flow rate and transport in larger species, including humans.…”

Section: Cervical Lymph Flow Rate Is Allometrically Scaled Across Rat...mentioning

confidence: 87%

“…In previously conducted studies by our laboratory, mesenteric and thoracic lymph flow rates were shown to scale allometrically across species (mouse, rat, dog and human) with an exponent of ~0.9, i.e. lymph flow rate increases in direct proportion to increases in body mass to the power of 0.9 (Trevaskis et al, 2020). Using the same calculations for allometric analysis (Trevaskis et al, 2020), the scaling exponent for cervical lymph flow rate from one side was 0.8 across species (rats, rabbits, cats and sheep).…”

Section: Cervical Lymph Flow Rate Is Allometrically Scaled Across Rat...mentioning

confidence: 94%

Development and application of a novel cervical lymph collection method to assess lymphatic transport in rats

et al. 2023

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Background: Fluids, solutes and immune cells have been demonstrated to drain from the brain and surrounding structures to the cervical lymph vessels and nodes in the neck via meningeal lymphatics, nasal lymphatics and/or lymphatic vessels associated with cranial nerves. A method to cannulate the efferent cervical lymph duct for continuous cervical lymph fluid collection in rodents has not been described previously and would assist in evaluating the transport of molecules and immune cells from the head and brain via the lymphatics, as well as changes in lymphatic transport and lymph composition with different physiological challenges or diseases.Aim: To develop a novel method to cannulate and continuously collect lymph fluid from the cervical lymph duct in rats and to analyze the protein, lipid and immune cell composition of the collected cervical lymph fluid.Methods: Male Sprague-Dawley rats were cannulated at the carotid artery with or without cannulation or ligation at the cervical lymph duct. Samples of blood, whole lymph and isolated lipoprotein fractions of lymph were collected and analyzed for lipid and protein composition using commercial kits. Whole lymph samples were centrifuged and isolated pellets were stained and processed for flow cytometry analysis of CD3+, CD4+, CD8a+, CD45R+ (B220) and viable cell populations.Results: Flow rate, phospholipid, triglyceride, cholesterol ester, free cholesterol and protein concentrations in cervical lymph were 0.094 ± 0.014 mL/h, 0.34 ± 0.10, 0.30 ± 0.04, 0.07 ± 0.02, 0.02 ± 0.01 and 16.78 ± 2.06 mg/mL, respectively. Protein was mostly contained within the non-lipoprotein fraction but all lipoprotein types were also present. Flow cytometry analysis of cervical lymph showed that 67.1 ± 7.4% of cells were CD3+/CD4+ T lymphocytes, 5.8 ± 1.6% of cells were CD3+/CD8+ T lymphocytes, and 10.8 ± 4.6% of cells were CD3-/CD45R+ B lymphocytes. The remaining 16.3 ± 4.6% cells were CD3-/CD45- and identified as non-lymphocytes.Conclusion: Our novel cervical lymph cannulation method enables quantitative analysis of the lymphatic transport of immune cells and molecules in the cervical lymph of rats for the first time. This valuable tool will enable more detailed quantitative analysis of changes to cervical lymph composition and transport in health and disease, and could be a valuable resource for discovery of biomarkers or therapeutic targets in future studies.

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“…Both absolute and relative bioavailability via lymph increase with increasing bodyweight of animal species tested (dog > rat > mouse; Trevaskis et al, 2013). Using recently published allometric scaling formulas (Trevaskis et al, 2020), abiraterone F AL in humans could be expected approximately fourfold higher than in rats, meaning 0.60% for the capsule formulation. Given the low absolute bioavailability, this could result in F RL of 10–15% in men.…”

Section: Discussionmentioning

confidence: 99%

Validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport of drugs

Ryšánek

Grus

Kozlík

et al. 2021

British J Pharmacology

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Background and purpose Lymphatic transport of drugs after oral administration is an important mechanism for absorption of highly lipophilic compounds. Direct measurement in lymph duct cannulated animals is the gold standard method, but non‐invasive cycloheximide chylomicron flow blocking method has gained popularity recently. However, concerns about its reliability have been raised. The aim of this work was to investigate the validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport using model compounds with high to very high lipophilicity, that is, abiraterone and cinacalcet. Experimental approach Series of pharmacokinetic studies were conducted with abiraterone acetate and cinacalcet hydrochloride after enteral/intravenous administration to intact, lymph duct cannulated and/or cycloheximide pre‐treated rats. Key results Mean total absolute oral bioavailability of abiraterone and cinacalcet was 7.0% and 28.7%, respectively. There was a large and significant overestimation of the lymphatic transport extent by the cycloheximide method. Mean relative lymphatic bioavailability of abiraterone and cinacalcet in cycloheximide method was 28‐fold and 3‐fold higher than in cannulation method, respectively. Conclusion and implications Cycloheximide chylomicron flow blocking method did not provide reliable results on lymphatic absorption and substantially overestimated lymphatic transport for both molecules, that is, abiraterone and cinacalcet. This non‐invasive method should not be used for the assessment of lymphatic transport and previously obtained data should be critically revised.

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Intestinal Lymph Flow, and Lipid and Drug Transport Scale Allometrically From Pre-clinical Species to Humans

Cited by 29 publications

References 47 publications

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

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

Development and application of a novel cervical lymph collection method to assess lymphatic transport in rats

Validity of cycloheximide chylomicron flow blocking method for the evaluation of lymphatic transport of drugs

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