Author: Suzanne Mary Caliph
Publisher:
Published: 2013
Total Pages: 524
ISBN-13:
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Highly lipophilic and poorly water soluble drug candidates are common outcomes ofdrug discovery programs in recent years, presenting drug development challenges throughpoor gastrointestinal absorption and insufficient systemic exposure after oral administration.Co-administration with lipidic excipients presents an apparent strategy to improve the oralbioavailability of these compounds by stimulating enhanced solubilisation in the gut andrecruitment of intestinal lymphatic drug transport. The impact of stimulating intestinallymphatic transport to improve oral bioavailability on systemic drug exposure, clearance anddeposition has been poorly understood. The interpretation of lymphatic drug transport data isfurther complicated by variations in dosing excipients and dispersed states, study models,prandial (fed/fasted) states, intravenous dosing conditions and formulations used for theassessment of absolute bioavailability. The studies described in this thesis investigatedvarious factors affecting the intestinal lymphatic transport and oral bioavailability assessmentof highly lipophilic compounds using lymph-cannulated and non lymph-cannulated animals.These factors examined included subtle differences in lipophilicity and lipid solubility ofchemically similar drug analogues, lipid and non-lipid based oral formulations, intravenousdosing states and dosing conditions. The impact of lymphatic drug delivery on systemicexposure, clearance and drug deposition was also examined in comparison with portal routeof drug absorption in this thesis. Oral bioavailability of highly lipophilic analogues wassignificantly enhanced after administration in long chain lipid-based formulations viastimulation of intestinal lymphatic transport and significantly influenced by subtle differencesin lipid solubility, however, not lipophilicity as indicated by log P. After delivery in lymph orthe lipid-based emulsion, systemic clearance (Cl) and volume of distribution (Vd) of a highlylipophilic, lymphatically transported model drug, halofantrine (Hf) were significantly lowerthan when delivered in plasma or lipid-free co-solvent formulation. However, where drug andlipid entered the systemic circulation coincidentally, Cl and Vd were unaffected by the routeof entry, but significantly altered by total plasma lipid levels. These findings suggest that amismatch in plasma lipid levels after intravenous and oral administration may lead todifferences in drug clearance and errors in bioavailability assessment. This thesis alsoinvestigated the influence of absorption route (lymphatics vs. blood) on drugpharmacokinetics and tissue distribution. Brain to blood ratios were found to be significantlylower after stimulation of intestinal lymphatic delivery suggesting that drug association withintestinal lymph lipoproteins might limit brain drug access. Lipophilic model compounds(DDT, Hf) and lipids were assessed following delivery to the systemic circulation inassociation with lymph lipoproteins or plasma, and were found to differ significantly. ForDDT, Cl and Vd were higher whereas for Hf, these parameters were lower due, in particular,to differences in adipose tissue uptake and liver uptake. For compounds like DDT, changes tothe route of absorption may thus directly impact on pharmacokinetics and tissue distribution,whereas for Hf, factors which influence lymphatic transport may, by altering systemiclipoprotein concentrations, indirectly impact pharmacokinetics and tissue distribution.Ultimately, careful control of dosing conditions and thus the extent of lymphatic transportmay be important in assuring reproducible efficacy and toxicity for lymphatically transporteddrugs.
