OBJECTIVE Available information on the background of the current state and advances of the intestinal lymph transport of medicines were reviewed. Drug transported by the intestinal lymphatic system can avoid hepatic first-pass metabolism,increase the bioavalibitlty of the highly lipophilic drug,and it is of importance for immunomodulatory,anticancer and anti-infective drugs. METHODS We conducted a systematic literature review of articles published recent years,analysis and summaries are made upon the advances and methods applied for the increase of the intestinal lymph transport. RESULTS AND CONCLUSION Intestinal lymphatic transport can increase the bioavailability via a reduction in the first-pass metabolism and the possibility of specifically targeting drugs to regions of the lymphatics,thus it is very advantageous for drugs that are under significant first-pass metabolism. The present review embodies a brief background of the mechanism of access of drugs to the intestinal lymph,a discussion on the links between lipid absorption and transport of highly lipophilic drugs,and approaches for enhancing lymphatic drug transport. Finally,experimental models of the lymphatic transport are also discussed.
CAI Qing-qing,LI Zhong-dong.
A Review on Intestinal Lymphatic Drug Transport[J]. Chinese Pharmaceutical Journal, 2013, 48(17): 1433-1438 https://doi.org/10.11669/cpj.2013.17.003
[1] CHOY Y B,PRAUSNITZ M R.The rule of five for non-oral routes of drug delivery: Ophthalmic,inhalation and transdermal .Pharmaceut Res,2011,28(5):943-948.[2] GURSOY R N,BENITA S.Self-emulsifying drug delivery systems (sedds) for improved oral delivery of lipophilic drugs .Biomed Pharmacother,2004,58(3):173-182.[3] PORTER C J,TREVASKIS N L,CHARMAN W N.Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs .Nat Rev Drug Discov,2007,6(3):231-248.[4] CHARMAN S A,SEGRAVE A M,EDWARDS G A,et al. Systemic availability and lymphatic transport of human growth hormone administered by subcutaneous injection .J Pharm Sci,2000,89(2):168-177.[5] MCLENNAN D N,PORTER C H,EDWARDS G A,et al. Lymphatic absorption is the primary contributor to the systemic availability of epoetin alfa following subcutaneous administration to sheep .J Pharmacol Exp Ther,2005,313(1):345-351.[6] TREVASKIS N L,CHARMAN W N,PORTER C J.Targeted drug delivery to lymphocytes: A route to site-specific immunomodulation.Molecular Pharmaceutics,2010,7(6):2297-2309.[7] CHAKRABORTY S,SHUKLA D,MISHRA B,et al. Lipid - an emerging platform for oral delivery of drugs with poor bioavailability .Eur J Pharm Biopharm,2009,73(1):1-15.[8] CHAI X Y,TAO T.Studies on the lipids increasing the intestinal lymphatic transport of drug .Chin Pharm J(中国药学杂志),2008,143(22):1681-1684.[9] TREVASKIS N L,CHARMAN W N,PORTER C J.Lipid-based delivery systems and intestinal lymphatic drug transport: A mechanistic update .Adv Drug Delivery Rev,2008,60(6):702-716. O′DRISCOLL C M.Lipid-based formulations for intestinal lymphatic delivery .Eur J Pharm Sci,2002,15(5):405-415. CALIPH S M,TREVASKIS N L,CHARMAN W N,et al. Intravenous dosing conditions may affect systemic clearance for highly lipophilic drugs: Implications for lymphatic transport and absolute bioavailability studies .J Pharm Sci,2012,101(9):3540-3546. GERSHKOVICH P,SHTAINER D,HOFFMAN A.The effect of a high-fat meal on the pharmacodynamics of a model lipophilic compound that binds extensively to triglyceride-rich lipoproteins .Int J Pharm,2007,333(1-2):1-4. CENSE H A,VAN EIJCK C H J,TILANUS H W.New insights in the lymphatic spread of oesophageal cancer and its implications for the extent of surgical resection .Best Pract Res Cl Ga,2006,20(5):893-906. UMEDA M,MARUSAWA H,SENO H,et al. Hepatitis Bvirus infection in lymphatic tissues in inactive hepatitis Bcarriers .J Hepatol,2005,42(6):806-812. YANEZ J A,WANG S W J,KNEMEYER I W,et al. Intestinal lymphatic transport for drug delivery .Adv Drug Delivery Rev,2011,63(10-11):923-942. KELLEHER A D,ZAUNDERS J J.Decimated or missing in action: Cd4+ t cells as targets and effectors in the pathogenesis of primary hiv infection .Current HIV/AIDS Reports,2006,3(1):5-12. TREVASKIS N L,CHARMAN W N,PORTER C J H.Acute hypertriglyceridemia promotes intestinal lymphatic lipid and drug transport: A positive feedback mechanism in lipid and drug absorption .Molecular Pharmaceutics,2011,8(4):1132-1139. BAUER E,JAKOB S,MOSENTHIN R.Principles of physiology of lipid digestion .Asian Austral J Anim,2005,18(2):282-295. KOHAN A,YODER S,TSO P.Lymphatics in intestinal transport of nutrients and gastrointestinal hormones.Ann N Y Acad Sci,2010,1207:44-51. LINDQUIST S,HERNELL O.Lipid digestion and absorption in early life: An update .Current Opin Clin Nutr Metab Care,2010,13(3):314-320. NORDSKOG B K,PHAN C T,NUTTING D F,et al. An examination of the factors affecting intestinal lymphatic transport of dietary lipids .Adv Drug Delivery Rev,2001,50(1-2):21-44. TREVASKIS N L,PORTER C J H,CHARMAN W N.The lymph lipid precursor pool is a key determinant of intestinal lymphatic drug transport .J Pharmacol Exp Ther,2006,316(2):881-891. TREVASKIS N L,MCEVOY C L,MCINTOSH M P,et al. The role of the intestinal lymphatics in the absorption of two highly lipophilic cholesterol ester transfer protein inhibitors (cp524,515 and cp532,623) .Pharmaceut Res,2010,27(5):878-893. TREVASKIS N L,SHANKER R M,CHARMAN W N,et al. The mechanism of lymphatic access of two cholesteryl ester transfer protein inhibitors (cp524,515 and cp532,623) and evaluation of their impact on lymph lipoprotein profiles .Pharmaceut Res,2010,27(9):1949-1964. KHOO S M,EDWARDS G A,PORTER C J,et al. A conscious dog model for assessing the absorption,enterocyte-based metabolism,and intestinal lymphatic transport of halofantrine .J Pharm Sci,2001,90(10):1599-1607. GERSHKOVICH P,HOFFMAN A.Effect of a high-fat meal on absorption and disposition of lipophilic compounds: The importance of degree of association with triglyceride-rich lipoproteins .Eur J Pharm Sci,2007,32(1):24-32. WHITE K L,NGUYEN G,CHARMAN W N,et al. Lymphatic transport of methylnortestosterone undecanoate (mu) and the bioavailability of methylnortestosterone are highly sensitive to the mass of coadministered lipid after oral administration of mu .J Pharmacol Exp Ther,2009,331(2):700-709. TREVASKIS N L,SHACKLEFORD D M,CHARMAN W N,et al. Intestinal lymphatic transport enhances the post-prandial oral bioavailability of a novel cannabinoid receptor agonist via avoidance of first-pass metabolism .Pharmaceut Res,2009,26(6):1486-1495. HOLM R,PORTER C J H,EDWARDS G A,et al. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (smedds) containing structured triglycerides .Eur J Pharm Sci,2003,20(1):91-97. WU H F,ZHOU A,LU C H,et al. Examination of lymphatic transport of puerarin in unconscious lymph duct-cannulated rats after administration in microemulsion drug delivery systems .Eur J Pharm Sci,2011,42(4):348-353. GRIFFIN B T,ODRISCOLL C M.A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model .J Pharm Pharmacol,2006,58(7):917-925. LING S S N,MAGOSSO E,KHAN N A K,et al. Enhanced oral bioavailability and intestinal lymphatic transport of a hydrophilic drug using liposomes .Drug Dev Ind Pharm,2006,32(3):335-345. PORTER C J H,CHARMAN W N.Preface - transport and absorption of drugs via the lymphatic system .Adv Drug Delivery Rev,2001,50(1-2):1-2. HOLM R,MULLERTZ A,PEDERSEN G P,et al. Comparison of the lymphatic transport of halofantrine administered in disperse systems containing three different unsaturated fatty acids .Pharmaceut Res,2001,18(9):1299-1304. FAISAL W,O′DRISCOLL C M,GRIFFIN B T.Bioavailability of lycopene in the rat: The role of intestinal lymphatic transport .J Pharm Pharmacol,2010,62(3):323-331. HUMBERSTONE A J,CHARMAN W N.Lipid-based vehicles for the oral delivery of poorly water soluble drugs .Adv Drug Delivery Rev,1997,25(1):103-128. MUROTA K,CERMAK R,TERAO J,et al. Influence of fatty acid patterns on the intestinal absorption pathway of quercetin in thoracic lymph duct-cannulated rats.Br J Nutr,2012,109(12):2147-2153. CALIPH S M,CHARMAN W N,PORTER C J H.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,2000,89(8):1073-1084. CHARMAN W N A,STELLA V J.Effects of lipid class and lipid vehicle volume on the intestinal lymphatic transport of ddt .Int J Pharm,1986,33(1-3):165-172. PORTER C J H,CHARMAN S A,HUMBERSTONE A J,et al. Lymphatic transport of halofantrine in the conscious rat when administered as either the free base or the hydrochloride salt: Effect of lipid class and lipid vehicle dispersion .J Pharm Sci,1996,85(4):357-361. CHARMAN W N A,STELLA V J.Estimating the maximal potential for intestinal lymphatic transport of lipophilic drug molecules .Int J Pharm,1986,34(1-2):175-178. KARPF D M,HOLM R,KRISTENSEN H G,et al. Influence of the type of surfactant and the degree of dispersion on the lymphatic transport of halofantrine in conscious rats .Pharmaceut Res,2004,21(8):1413-1418. SEEBALLUCK F,ASHFORD M B,ODRISCOLL C M.The effects of pluronic (r) block copolymers and cremophor (r) el on intestinal lipoprotein processing and the potential link with p-glycoprotein in caco-2 cells .Pharmaceut Res,2003,20(7):1085-1092. CHARMAN W N,PORTER C J H.Lipophilic prodrugs designed for intestinal lymphatic transport .Adv Drug Delivery Rev,1996,19(2):149-169. SHACKLEFORD D M,FAASSEN W A,HOUWING N,et al. Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs .J Pharmacol Exp Ther,2003,306(3):925-933. GERSHKOVICH P,QADRI B,YACOVAN A,et al. Different impacts of intestinal lymphatic transport on the oral bioavailability of structurally similar synthetic lipophilic cannabinoids: Dexanabinol and prs-211,220 .Eur J Pharm Sci,2007,31(5):298-305. TSAI Y J,TSAI T H.Mesenteric lymphatic absorption and the pharmacokinetics of naringin and naringenin in the rat .J Agr Food Chem,2012,60(51):12435-12442. CHEN S A,SAWCHUK R J,BRUNDAGE R C,et al. Plasma and lymph pharmacokinetics of recombinant human interleukin-2 and polyethylene glycol-modified interleukin-2 in pigs .J Pharmacol Exp Ther,2000,293(1):248-259. MCLENNAN D N,PORTER C J H,EDWARDS G A,et al. The absorption of darbepoetin alfa occurs predominantly via the lymphatics following subcutaneous administration to sheep .Pharmaceut Res,2006,23(9):2060-2066. EDWARDS G A,PORTER C J H,CALIPH S M,et al. Animal models for the study of intestinal lymphatic drug transport .Adv Drug Delivery Rev,2001,50(1-2):45-60. DAHAN A,HOFFMAN A.Evaluation of a chylomicron flow blocking approach to investigate the intestinal lymphatic transport of lipophilic drugs .Eur J Pharm Sci,2005,24(4):381-388. SUN M,ZHAI X,XUE K,et al. Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (spip) technique and a chylomicron flow blocking approach: Linear correlation with oral bioavailabilities in rats .Eur J Pharm Sci,2011,43(3):132-140. KARPF D M,HOLM R,GARAFALO C,et al. Effect of different surfactants in biorelevant medium on the secretion of a lipophilic compound in lipoproteins using caco-2 cell culture .J Pharm Sci,2006,95(1):45-55. SEEBALLUCK F,LAWLESS E,ASHFORD M B,et al. 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 .Pharmaceut Res,2004,21(12):2320-2326. HOLM R,HOEST J.Successful in silico predicting of intestinal lymphatic transfer .Int J Pharm,2004,272(1-2):189-193.
