The role of the lymphatic system in subcutaneous absorption of macromolecules in the rat model

Kagan, Leonid; Gershkovich, Pavel; Mendelman, Avivit; Amsili, Sofia; Ezov, Nathan; Hoffman, Amnon

doi:10.1016/j.ejpb.2007.04.002

Cited by 90 publications

(89 citation statements)

References 23 publications

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“…Because of the technical challenges of cannulating lymph vessels in smaller-sized laboratory animals, there have been very limited reports on the contribution of the lymphatic system in subcutaneous absorption of macromolecules in commonly used preclinical species. Unfortunately, the few available reports in rats and rabbits presented contradictory evidence (Bocci et al, 1986(Bocci et al, , 1988Kojima et al, 1988;Kagan et al, 2007). In the more recent report by Kagan et al (2007), the contribution of the lymphatic system to subcutaneous absorption of macromolecules was systematically examined in a rat thoracic lymph duct cannulation (LDC) model, using bovine insulin (5.6 kDa), recombinant human erythropoietin (EPO) (30.4 kDa), and bovine albumin (66 kDa) as model compounds.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the few available reports in rats and rabbits presented contradictory evidence (Bocci et al, 1986(Bocci et al, , 1988Kojima et al, 1988;Kagan et al, 2007). In the more recent report by Kagan et al (2007), the contribution of the lymphatic system to subcutaneous absorption of macromolecules was systematically examined in a rat thoracic lymph duct cannulation (LDC) model, using bovine insulin (5.6 kDa), recombinant human erythropoietin (EPO) (30.4 kDa), and bovine albumin (66 kDa) as model compounds. The results suggested minimal contribution of the lymphatic system for all three molecules, regardless of their molecular masses, i.e., minimal reduction of serum exposure in the thoracic LDC animals, and Ͻ3% drug recovery in thoracic duct lymph (Kagan et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Wang¹,

Chen²,

Shen³

et al. 2012

Drug Metab Dispos

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ABSTRACT:The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ϳ70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2-to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Wang¹,

Chen²,

Shen³

et al. 2012

Drug Metab Dispos

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“…There is a substantial interest in utilizing s.c. delivery for monoclonal antibodies (mAbs) to improve patient convenience and potentially reduce treatment costs (Aue et al, 2010;Bittner and Schmidt, 2012;Richter et al, 2012). Mechanisms of mAb absorption after s.c. administration are not fully understood but are influenced by several kinetic processes, including transport through the extracellular matrix, uptake by the blood and lymphatic capillaries, and presystemic elimination (Porter and Charman, 2000;Swartz, 2001;Kagan et al, 2007). Experimental perturbation coupled with mathematical modeling is needed to resolve the relative contribution of these components to overall mAbs absorption.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Kagan

Mager

2012

Drug Metab Dispos

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Absorption of monoclonal antibodies (mAbs) after s.c. injection results from the interplay among several kinetic processes. The aims of this study were to investigate the absorption mechanisms of rituximab in rats by using slow s.c. infusion and coadministration with nonspecific IgG or hyaluronidase, and to evaluate the predictive performance of the pharmacokinetic model previously developed to describe the nonlinear absorption behavior of mAbs. Rituximab serum concentrations were measured after s.c. coadministration with nonspecific IgG and hyaluronidase to rats. Several dose levels and different injection sites were evaluated. For the back site, 6.5-and 2.6-fold decreases in the area under the concentration-time curve were obtained after coadministration with IgG for 1 and 10 mg/kg doses compared with administration of rituximab alone. For the abdomen, only a minor reduction in concentrations was observed. Hyaluronidase increased the rate of s.c. absorption and the bioavailability (1.9-and 1.6-fold for the back and the abdomen injection of 10 mg/kg). Our previously established pharmacokinetic model provided excellent predictions of the effect of nonspecific IgG on rituximab absorption. In conclusion, the magnitude of the effect of absorption modifiers is dependent on the site of injection and the dose level of rituximab. Pharmacokinetic profiles further support the hypothesis that neonatal Fc receptormediated transport is a major determinant of s.c. absorption of mAbs.

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“…92 Small animals, such as rats, are commonly used, but some larger animals, including sheep, pigs, rabbits, and dogs, have also been used for this model. [92][93][94][95][96][97][98][99][100] Another in vivo model is the lymphatic venous shunt, in which drug concentrations in lymph are measured at fixed time intervals, and lymph is collected over a longer period of time. Further, an indirect method has been used in an oral bioavailability study to evaluate intestinal lymphatic drug transport in both the presence and absence of inhibitors of intestinal chylomicron flow.…”

Section: Models Used To Study Drug Transport In the Lymphatic System mentioning

confidence: 99%

Advanced drug delivery to the lymphatic system: lipid-based nanoformulations

Khan

Mudassir²,

Mohtar³

et al. 2013

IJN

131

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Abstract:The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipidbased nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes (subcutaneous, pulmonary, and intestinal) for targeting of the lymphatic system. This paper provides a detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system. Physicochemical properties that influence lymphatic delivery as well as the advantages of lipid-based nanoformulations for lymphatic delivery are also discussed.

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The role of the lymphatic system in subcutaneous absorption of macromolecules in the rat model

Cited by 90 publications

References 23 publications

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Advanced drug delivery to the lymphatic system: lipid-based nanoformulations

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