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

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Abstract

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 Vd 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 Vd 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 Vd. 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. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2395-2408, 2013.
Original languageEnglish
Pages (from-to)2395 - 2408
Number of pages14
JournalJournal of Pharmaceutical Sciences
Volume102
Issue number7
DOIs
Publication statusPublished - 2013

Cite this

@article{04a5b2967a084fbbbe0a8e18ab892daa,
title = "The impact of lymphatic transport on the systemic disposition of lipophilic drugs",
abstract = "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 Vd 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 Vd 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 Vd. 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. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2395-2408, 2013.",
author = "Caliph, {Suzanne Mary} and Enyuan Cao and Bulitta, {Jurgen Bernd} and Luojuan Hu and Sifei Han and Porter, {Christopher John} and Natalie Trevaskis",
year = "2013",
doi = "10.1002/jps.23597",
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The impact of lymphatic transport on the systemic disposition of lipophilic drugs. / Caliph, Suzanne Mary; Cao, Enyuan; Bulitta, Jurgen Bernd; Hu, Luojuan; Han, Sifei; Porter, Christopher John; Trevaskis, Natalie.

In: Journal of Pharmaceutical Sciences, Vol. 102, No. 7, 2013, p. 2395 - 2408.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The impact of lymphatic transport on the systemic disposition of lipophilic drugs

AU - Caliph, Suzanne Mary

AU - Cao, Enyuan

AU - Bulitta, Jurgen Bernd

AU - Hu, Luojuan

AU - Han, Sifei

AU - Porter, Christopher John

AU - Trevaskis, Natalie

PY - 2013

Y1 - 2013

N2 - 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 Vd 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 Vd 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 Vd. 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. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2395-2408, 2013.

AB - 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 Vd 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 Vd 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 Vd. 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. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2395-2408, 2013.

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