Intestinal lymphatics

As a generalization, to be orally well absorbed a compound must be soluble in the contents of the gastrointestinal lumen [4]. Solubility in aqueous buffer is commonly used as a simpHfying surrogate for intestinal content solubility. There are rare exceptions to the principle that to be absorbed a compound must be soluble. SoHd particles, e.g. starch, can be absorbed. Absorption of very small quantities of even biologically very large compounds can occur via lymphoid tissue, e.g. orally active vaccines. Very hpophihc basic compounds, e.g. certain antimalarials, can be absorbed via the intestinal lymphatics and dehvered directly to the heart... 

Porter CJ and Charman WN (2001) Intestinal Lymphatic Drug Transport An Update. Adv Drug Deliv Rev 50 pp 61-80. 

Griffin BT and O Driscoll CM (2006) A Comparison of Intestinal Lymphatic Transport and Systemic Bioavailability of Saquinavir from Three Lipid-Based Formulations in the Anaesthetised Rat Model. J Pharm Pharmacol 58 pp 917-925. 

Charman WN and Stella VJ (1986) Estimating the Maximal Potential for Intestinal Lymphatic Transport of Lipophilic Drug Molecules. Int J Pharm 34 pp 175-178. 

Khoo SM, Shackleford DM, Porter CJ, Edwards GA and Charman WN (2003) Intestinal Lymphatic Transport of Halofantrine Occurs After Oral Administration of a Unit-Dose Lipid-Based Formulation to Fasted Dogs. Pharm Res 20 pp 1460-1465. 

Pharmacokinetics Phytonadione is only absorbed from the Gl tract via intestinal lymphatics in the presence of bile salts. Although initially concentrated in the liver, vitamin K is rapidly metabolized, and very little tissue accumulation occurs. Parenteral phytonadione is generally detectable within 1 to 2 hours. Phytonadione usually controls hemorrhage within 3 to 6 hours. A normal prothrombin level may be obtained in 12 to 14 hours. Oral phytonadione exerts its effect in 6 to 10 hours. 

Seeballuck, F., Lawless, E., Ashford, M. B., and O Driscoll, C. M. (2004). Stimulation of triglyceride-rich lipoprotein secretion by polysorbate 80 In vitro and in vivo correlation using Caco-2 cells and a cannulated rat intestinal lymphatic model. Pharm. Res. 21, 2320-2326. 

Norkskog, B.K. et al. (2001) An examination of the factors affecting intestinal lymphatic transport of dietary lipids. Adv. Drug Del. Rev., 50 21-44. 

Porter, C.J.H. andCharman, W.N. (1997) Uptake of drugs into the intestinal lymphatics after oral administration. Adv. Drug Del. Rev., 25 71-89. 

Bioavailability of lipophilic drugs may be enhanced also by the stimulation of the intestinal lymphatic transport pathway. This issue will be addressed separately (Section 6.3.2.1). 

FIGURE 6.5 Relationship between the extent of intestinal lymphatic transport of a drug and lipophilicity after oral administration. (From Stella, VJ. and Pochopin, N.L. Lymphatic Transport of Drugs, Charman, W.N. and Stella, V.J., Eds., CRC Press, Boca Raton, 1992, p. 181. With permission.)... 

The majority of orally administered drugs gain access to the systemic circulation by direct absorption into the portal blood. However, highly lipophilic compounds may reach the systemic blood circulation via the intestinal lymphatic system. The overall bioavailability of... 

Following oral administration of a lipophilic drug, the main route for the drug to access into the intestinal lymphatics is transcellular, by tracking the same pathway as the lipidic nutrients in food, which use the physiological intestinal lipid transport system. Hence, a brief description of this process is described. 

Intestinal lymphatic transport has also been shown to substantially contribute to the absorption of fat-soluble vitamins [91], ontazolast [26], probucol [16] and others. 

As reviewed in this chapter, certain means can be utilized to improve the bioavailability of lipophilic drugs, whether by formulative approach or molecular changes strategies. These means present a number of attractive propositions to the scientist, ranging from an enhancement of drug dissolution and solubilization by lipid-based formulation, increased solubility via the synthesis of a prodrug, specific delivery to the intestinal lymphatics, and reduction in enterocyte-hepatic presystemic metabolism and efflux systems. 

Charman, W.N., and V.J. Stella. 1986. Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules. Int J Pharm 34 175. 

Stella, V.J., and N.L. Pochopin. 1992. Lipophilic prodrugs and the promotion of intestinal lymphatic drug transport. In Lymphatic transport of drugs, eds. W.N. Charman, and Y J. Stella, 181. Boca Raton CRC Press. 

Dahan, A., and A. Hoffman. 2005. Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs. Eur J Pharm Sci 24 381. 

Caliph, S.M., W.N. Charman, and C.J.H. Porter. 2000. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J Pharm Sci 89 1073. 

Cheema, M., K.J. Palin, and S.S. Davis. 1987. Lipid vehicles for intestinal lymphatic drug absorption. J Pharm Pharmacol 39 55. 

Khoo, S.M., et al. 2001. A conscious dog model for assessing the absorption, enterocyte-based metabolism, and intestinal lymphatic transport of halofantrine. J Pharm Sci 90 1599. 

Edwards, G.A., et al. 2001. Animal models for the study of intestinal lymphatic drug transport. Adv Drug Deliv Rev 50 45. 

Gershkovich, P., and A. Hoffman. 2005. Uptake of lipophilic drugs by plasma derived isolated chylomicrons Linear correlation with intestinal lymphatic bioavailability. Fur J Pharm Sci 26 394. 

By enhancing the formation and turnover of lymph lipoproteins through the enterocyte and provoking, or improving, the targeting of orally administered lipophilic drugs to the intestinal lymphatics. 

In this chapter we will provide a brief overview of the early approaches to bioavailability enhancement by use of simple lipid-based delivery systems (lipid solutions, emulsions etc), and then describe recent progress in the application of self-emulsifying- and microemulsion-based formulations. The effects of lipids on the oral bioavailability of co-administered poorly water-soluble drugs may also be classified from a mechanistic (and to a degree, historical) perspective as physicochemically mediated effects (solubility, dissolution, surface area) and biochemically mediated effects (metabolism, transport related events), and these will be approached separately. It is readily apparent, however, that in many cases physicochemically and biochemically mediated mechanisms will operate side by side. In some instances, bioavailability may also be enhanced by the stimulation of intestinal lymphatic transport, and these studies will be addressed in a separate section. 

After absorption, most drugs and xenobiotics traverse the enterocyte and are absorbed into the portal blood. A small number of highly lipophilic drugs, however, are transported to the systemic circulation by means of the intestinal lymphatics. 

The potential for orally administered drugs to enter the intestinal lymphatics is therefore defined by their selectivity for uptake into the intestinal lymphatics as opposed to the blood capillaries in the subepithelial space. Because selectivity for the lymphatics is primarily defined by size, it is apparent that only macromolecules or colloids will be preferentially absorbed into the intestinal lymphatics. However, the intestine provides a significant barrier to the absorption of both macromolecules and intact colloids, and the most prevalent mechanism for drug delivery to the intestinal lymph is by means of secondary drug association with intestinal lipoproteins [110]. The size of the drug-lipoprotein complex subsequently dictates absorption into the lymphatic vessels. 

Table 5 Summary of Recent Intestinal Lymphatic Transport Data (Lymphotropic Prodrugs Have not Been Included)... 

---