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The Mesenteric Lymph Duct Cannulated Rat Model: Application to the Assessment of Intestinal Lymphatic Drug Transport

The intestinal lymphatic system plays key roles in fluid transport, lipid absorption and immune function. Lymph flows directly from the small intestine ...

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.

Org 45697 (MW 600.7, ClogP 7,92, Soja-&Ouml;l-L&ouml;slichkeit 50 mg/g) und Org 46035 (MW 601,6, verstopfen P 8,46, Soja-&Ouml;l-L&ouml;slichkeit 40 mg/g) sind zwei schlecht Wasser l&ouml;slich (&lt; 0,1 &micro;g/ml), hochgradig lipophilen Medikament Kandidaten mit Immunmodulator Aktivit&auml;t und sehr &auml;hnliche chemische Strukturen. Nach oraler Verabreichung an bewusste ambulante Ratten in einer w&auml;ssrigen basierende Methylzellulose/Tween 80-Aufh&auml;ngung, die Bioverf&uuml;gbarkeit von beider Verbindungen gering war (&lt; 2 % der verabreichten dosis). Allerdings war die bioverf&uuml;gbarkeit deutlich erh&ouml;ht (&gt; 5 fach) nach oraler Gabe in einem langkettigen Triglyzeride Lipid (Oliven&ouml;l) Formulierung. Sp&auml;tere Studien haben untersucht das Potenzial f&uuml;r L&ouml;sungsmittel Rezepturen, einschlie&szlig;lich Lipid-basierte Formulierungen, um die orale Bioverf&uuml;gbarkeit von Org 45697 und Org 46035 zu verbessern und zweitens erkunden der potenzielle Beitrag von intestinalen lymphatischen transport zu intestinale Resorption. Die experimentellen Daten zeigen, dass L&ouml;sungsmittel Formulierungen vorsehen f&uuml;r betr&auml;chtliche Steigerungen der orale Bioverf&uuml;gbarkeit Org 45697 und Org 46035 und, nachdem die gleichzeitige Gabe mit Lipid, 35-50 % der absorbierten Dosis in den K&ouml;rperkreislauf &uuml;ber die intestinale Lymphe transportiert werden d&uuml;rfen. Interessanterweise war die lymphatische Bef&ouml;rderung von den weniger l&ouml;slichen Lipid-Analog, Org 46035 ca. 40 % niedriger als die der Org 45697 darauf hindeutet, dass relativ geringf&uuml;gige Unterschiede in Lipid L&ouml;slichkeit erhebliche Auswirkungen auf das Ausma&szlig; der lymphatischen Transport haben k&ouml;nnen.

Orale Bioverf&uuml;gbarkeit Bewertung und intestinalen lymphatischen Transport von Org 45697 und Org 46035, zwei hoch lipophilen neuartiger Immunmodulator Analoga.

The clearance (Cl) and volume of distribution (V(ss)) of a lipophilic, lymphatically transported drug, halofantrine (Hf) have been evaluated after intravenous delivery to the systemic circulation in ex vivo lymph and plasma, and compared with the data obtained after administration of a lipid-based emulsion and a lipid-free cosolvent formulation. Systemic Cl and V(ss) were significantly lower (approximately twofold) after delivery of Hf in lymph or the emulsion when compared with the administration in plasma or the cosolvent formulation. Preadministration of drug-free lymph, immediately before administration of drug in plasma, however, resulted in plasma profiles consistent with that obtained after administration of drug in lymph/emulsion. Where drug and lipid entered the systemic circulation coincidentally, systemic Cl of Hf, therefore, appeared to be relatively unaffected by the route of entry to the systemic circulation (i.e. via the lymph or the blood), but more significantly altered by total plasma lipid levels. Because temporal changes to plasma lipid levels occur as a result of the absorption of formulation or food-derived lipids and the infusion of intravenous lipid emulsions, the current data suggest that a mismatch in plasma lipid levels after intravenous and oral administrations may lead to differences in drug Cl and errors in bioavailability assessment.

Intravenous dosing conditions may affect systemic clearance for highly lipophilic drugs: implications for lymphatic transport and absolute bioavailability studies.

To establish a lymph-cannulated mouse model, and use the model to investigate the impact of lipid dose on exogenous and endogenous lipid recruitment, and drug transport, into the lymph of males versus females. Finally, lymphatic transport and drug absorption in the mouse were compared to other pre-clinical models (rats/dogs).

A mouse model to evaluate the impact of species, sex, and lipid load on lymphatic drug transport.

This work investigates the influence of drug absorption route (intestinal lymphatics vs. blood supply) on drug pharmacokinetics and tissue distribution. To achieve this aim, the pharmacokinetics and tissue distribution of model compounds [1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane, DDT; halofantrine] and lipids were assessed following intravenous delivery in lymph lipoproteins or plasma, and were found to differ significantly. For DDT, the clearance (CL) and volume of distribution (Vd ) were higher, whereas for halofantrine, CL and V(d) were lower, after entry in lymph versus plasma due, in particular, to differences in adipose tissue and liver uptake. In a recent study, halofantrine CL and V(d) were similar following entry in lymph or entry in plasma into the systemic circulation of animals predosed with lymph, whereas in the current study, predosing lymph did not influence DDT CL and V(d). For compounds such as DDT, changes to the route of absorption may thus directly impact on pharmacokinetics and tissue distribution, whereas for halofantrine factors that influence lymphatic transport may, by altering systemic lipoprotein concentrations, indirectly impact pharmacokinetics and tissue distribution. Ultimately, careful control of dosing conditions (formulation, prandial state), and thus the extent of lymphatic transport, may be important in assuring reproducible efficacy and toxicity for lymphatically transported drugs.

The impact of lymphatic transport on the systemic disposition of lipophilic drugs.

To assess the role of intestinal lymphatic transport in the oral bioavailability and brain deposition of a highly lipophilic, centrally acting drug candidate (Org 49209) in comparison to cholesterol, a close structural analogue.

The influence of intestinal lymphatic transport on the systemic exposure and brain deposition of a novel highly lipophilic compound with structural similarity to cholesterol.

Cannulation of the thoracic lymph duct in experimental animals allows direct measurement of the lymphatic exposure of lymph-targeted drugs. When coupled with recent advances in genetically modified and diseased mouse models, this presents further opportunities to define changes in biological processes and disease in response to drug treatment. Although cannulation of the thoracic lymph duct in mice is inherently challenging because of the small size and delicate nature of the duct, it can be further confounded by anatomical variations between animals. In this communication, we present our observations on the anatomical features of the thoracic lymph duct between mice of different strains and genders, and discuss the impact of these features on the "cannulatability" of the duct. We also provide some technical tips to help guide other investigators to deliver higher experimental success rates. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1207-1209, 2015.

Practical lessons in murine thoracic lymph duct cannulations: observations in female and male mice across four different strains that impact on "cannulatability".

Article	Year
Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues. Current drug delivery\| PubMed ID: 19534711	2009
Intravenous dosing conditions may affect systemic clearance for highly lipophilic drugs: implications for lymphatic transport and absolute bioavailability studies. Journal of pharmaceutical sciences\| PubMed ID: 22623170	2012
A mouse model to evaluate the impact of species, sex, and lipid load on lymphatic drug transport. Pharmaceutical research\| PubMed ID: 23430484	2013
The impact of lymphatic transport on the systemic disposition of lipophilic drugs. Journal of pharmaceutical sciences\| PubMed ID: 23696002	2013
The influence of intestinal lymphatic transport on the systemic exposure and brain deposition of a novel highly lipophilic compound with structural similarity to cholesterol. The Journal of pharmacy and pharmacology\| PubMed ID: 24821499	2014
Practical lessons in murine thoracic lymph duct cannulations: observations in female and male mice across four different strains that impact on "cannulatability". Journal of pharmaceutical sciences\| PubMed ID: 25536935	2015

Suzanne M. Caliph

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