Intestinal Lymphatic Drug Transport Research Articles

Engineering Nano- and Microparticles as Oral Delivery Vehicles to Promote Intestinal Lymphatic Drug Transport.

Targeted oral delivery of a drug via the intestinal lymphatic system (ILS) has the advantages of protecting against hepatic first-pass metabolism of the drug and improving its pharmacokinetic performance. It is also a promising route for the oral delivery of vaccines and therapeutic agents to induce mucosal immune responses and treat lymphatic diseases, respectively. This article describes the anatomical structures and physiological characteristics of the ILS, with an emphasis on enterocytes and microfold (M) cells, which are the main gateways for the transport of particulate delivery vehicles across the intestinal epithelium into the lymphatics. A comprehensive overview of recent advances in the rational engineering of particulate vehicles, along with the challenges and opportunities that they present for improving ILS drug delivery, is provided, and the mechanisms by which such vehicles target and transport through enterocytes or M cells are discussed. The use of naturally sourced materials, such as yeast microcapsules and their derived polymeric β-glucans, as novel ILS-targeting delivery vehicles is also reviewed. Such use is the focus of an emerging field of research. Their potential use in the oral delivery of nucleic acids, such as mRNA vaccines, is proposed.

Lipid-Based Oral Formulation Strategies for Lipophilic Drugs.

Partition coefficient (log P) is a key physicochemical characteristic of lipophilic drugs which plays a significant role in formulation development for oral administration. Lipid-based formulation strategies can increase lymphatic transport of these drugs and can enhance bioavailability many folds. The number of lipophilic drugs in pharmacopoeias and under discovery are continuously increasing and making the job of the formulation scientist difficult to develop suitable formulation of these drugs due to potent nature and water insolubility of these drugs. Recently, many natural and synthetic lipids are appearing in the market which are helpful in the development of lipid-based formulations of these types of drugs having enhanced solubility and bioavailability. One such reason for this enhanced bioavailability is the accessibility of the lymphatic transport as well as avoidance of first-pass effect. This review discusses the impact of lipophilicity in enhancing the intestinal lymphatic drug transport thereby reducing first-pass metabolism. The most appropriate strategy for developing a lipid-based formulation depending upon the degree of lipophilicity has been critically discussed and provides information on how to develop optimum formulation. Various formulation strategies are discussed in-depth by classifying lipid-based oral drug delivery systems with case studies of few marketed formulations with challenges and opportunities for the future of the formulations.

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

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

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 via a series of lymphatic vessels and nodes that converge at the superior mesenteric lymph duct. Cannulation of the mesenteric lymph duct thus enables the collection of mesenteric lymph flowing from the intestine. Mesenteric lymph consists of a cellular fraction of immune cells (99% lymphocytes), aqueous fraction (fluid, peptides and proteins such as cytokines and gut hormones) and lipoprotein fraction (lipids, lipophilic molecules and apo-proteins). The mesenteric lymph duct cannulation model can therefore be used to measure the concentration and rate of transport of a range of factors from the intestine via the lymphatic system. Changes to these factors in response to different challenges (e.g., diets, antigens, drugs) and in disease (e.g., inflammatory bowel disease, HIV, diabetes) can also be determined. An area of expanding interest is the role of lymphatic transport in the absorption of orally administered lipophilic drugs and prodrugs that associate with intestinal lipid absorption pathways. Here we describe, in detail, a mesenteric lymph duct cannulated rat model which enables evaluation of the rate and extent of lipid and drug transport via the lymphatic system for several hours following intestinal delivery. The method is easily adaptable to the measurement of other parameters in lymph. We provide detailed descriptions of the difficulties that may be encountered when establishing this complex surgical method, as well as representative data from failed and successful experiments to provide instruction on how to confirm experimental success and interpret the data obtained.

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

The Lymph Lipid Precursor Pool Is a Key Determinant of Intestinal Lymphatic Drug Transport

The influence of the size and turnover kinetics of the enterocyte-based lymph lipid precursor pool (LLPP) on intestinal lymphatic drug transport has been examined. Mesenteric lymph duct-cannulated rats were infused intraduodenally with low (2-5 mg/h) or high (20 mg/h) lipid-dose formulations containing 100 microg/h halofantrine (Hf, a model drug) and 1 microCi/h (14)C-oleic acid (OA) (as a marker for lipid transport) until steady-state rates of lipid(dX(L)/dt)(ss) and drug (dD(L)/dt)(ss) transport in lymph were obtained. After 5 h, the infusion was changed to formulations of the same composition but excluding (14)C-OA and Hf, allowing calculation of the first order rate constants describing turnover of lipid (K(X)) and drug (K(D)) from the LLPP into the lymph from the washout kinetics. The mass of lipid (X(LP)) and drug (D(LP)) in the LLPP was also determined. Biliary-lipid output was determined in a separate group of rats that had been infused with the same formulations. The results indicate that after administration of high lipid doses, lymphatic drug transport is dependent on the mass of exogenous lipid available in the LLPP and the rate of lipid pool turnover into the lymph. In contrast, after administration of low lipid doses, biliary-derived endogenous lipids are most likely to be the primary drivers of drug incorporation into the LLPP and lymph. Therefore, the LLPP size and composition seem to be major determinants of lymphatic drug transport, and formulation components, which increase lipid pool size, may therefore enhance lymphatic drug transport.

Bile Increases Intestinal Lymphatic Drug Transport in the Fasted Rat

This study was conducted to determine the influence of (1) the source of recruited endogenous fatty acid (FA), and (2) bile on intestinal lymphatic transport of halofantrine (Hf) in fasted rats. Endogenous FA output in bile, and exogenous ((14)C radiolabeled) FA, endogenous FA, and Hf transport in mesenteric lymph were determined following administration of low dose lipid formulations containing either 4 or 40 mg of exogenous FA [oleic acid (OA)] and different amounts of bile salt (BS) and lysophosphatidylcholine (LPC) to fasted rats. Administration of 40 mg of OA recruited endogenous FA and Hf transport into intestinal lymph, whereas 4 mg OA did not. However, addition of BS to the 4-mg OA dose led to stimulation of endogenous FA recruitment into lymph and an increase in lymphatic transport of Hf and endogenous FA output in bile. Addition of LPC to the 4-mg OA dose (dispersed in BS) caused a substantial increase in endogenous FA transport in lymph; however, no coincident increase in either lymphatic transport of Hf or endogenous FA output in bile was observed. Biliary-derived endogenous FA has a higher propensity to support lymphatic transport of Hf compared to other sources of endogenous FA. The results suggest that this is related to the disparate trafficking of these alternate sources of endogenous FA within the enterocyte.

A stepwise surgical procedure to investigate the lymphatic transport of lipid-based oral drug formulations: Cannulation of the mesenteric and thoracic lymph ducts within the rat

Introduction: A number of animal models have been described for the assessment of intestinal lymphatic drug transport. Lymphatic transport studies are commonly first conducted in the laboratory rat, with larger more complicated models (i.e., dog or pig) subsequently investigated. However, the utility of lymph fistulation in large animals is limited by considerable logistical and economic constraints. Methods: This paper describes a stepwise surgical procedure for cannulating the thoracic and mesenteric lymph ducts in male Sprague–Dawley rats. Results: Following surgery, thoracic and mesenteric lymph flow rates during the 24-h period immediately following surgery averaged 12.5±2.5 and 2.4±1.1 ml/h, respectively. This flow rate is greater than that obtained with previously described methods, which require restraint of the animals and/or a 24-h recovery period and are reported to produce average intestinal lymph flow rates of 2 ml/h. Discussion: This animal model can be utilized for the assessment of drug transport by the lymphatics and for determining what percentage of lymphatic transport is a result of only intestinal lymphatics.

Model systems for intestinal lymphatic transport studies.

Transport via the intestinal lymphatic system has been shown to contribute to the absorption of a number of highly lipophilic xenobiotics (Yeung and von Saigent, 1972; Noguchi et al., 1985; Fukui et al., 1989; Ichihashi et al., 1991a). Although intestinal lymphatic drug transport leads directly to an increase in oral bioavailability, it also confers other potential advantages such as avoidance of hepatic first-pass metabolism, direct targeting to the associated lymphoid tissue, and indirect targeting to specific sites such as those associated with low-density lipoprotein receptors and lymphocytes (Bijsterbosch and van Berkel, 1990; Charman and Stella, 1991).

Testing potential dosage form strategies for intestinal lymphatic drug transport: studies in the rat

The effect of some differing formulation strategies on the intestinal lymphatic transport of DDT has been evaluated. Drug-lipid vehicle combinations were administered to conscious rats by the peroral route, or to anesthetized rats by intraduodenal infusion. A 2 mg dose of DDT was dissolved in either 200 μl of peanut oil (triglyceride) or 200 μl of oleic acid (fatty acid) and administered to mesenteric lymph duct cannulated rats. During the post-dosing period, there were no significant differences in the percent dose of DDT collected in intestinal lymph when administered in peanut oil by either the peroral (24.3 ± 3.0% dose) or intraduodenal route (19.9 ± 1.8% dose). When the same dose of DDT was administered in oleic acid, greater lymphatic transport occurred when the DDT-lipid vehicle combination was administered intraduodenally (35.7 ± 2.1% dose), rather than perorally (16.6 ± 3.3% dose). It is postulated that these differences may be due to differing effects of the fatty acid and triglyceride lipids on gastric emptying and/or intestinal motility. When considering that a drug product can release a drug-lipid combination at different sites within the gastrointestinal tract (stomach or small intestine), these results may have a bearing on potential formulation strategies and dosage form design for the enhancement of the lymphatic transport of lipophilic drugs. Simulated sustained release preparations using a 200 μl/8 h infusion of peanut oil containing 2 mg of DDT did not afford significantly enhanced lymphatic transport of DDT when compared to a 200 μ1/2 h infusion of the same drug-lipid combination. There was a large amount of variation in the lymphatic transport of DDT administered at the slower rate of infusion. When animals were pre-dosed with 75 μl of peanut oil prior to infusion of 2 mg DDT in 200 μl over 8 h, there was much less variability in the lymphatic transport of DDT. It appears that there may. be an optimal rate of lipid input into the small intestine to trigger, or initiate, significant lymphatic transport of lipophilic molecules.