An investigation of the impact of intestinal lymphatic transport on bioavailability, systemic clearance and disposition of lipophilic drugs

Highly lipophilic and poorly water soluble drug candidates are common outcomes of drug discovery programs in recent years, presenting drug development challenges through poor gastrointestinal absorption and insufficient systemic exposure after oral administration. Co-administration with lipidic excipients presents an apparent strategy to improve the oral bioavailability of these compounds by stimulating enhanced solubilisation in the gut and recruitment of intestinal lymphatic drug transport. The impact of stimulating intestinal lymphatic transport to improve oral bioavailability on systemic drug exposure, clearance and deposition has been poorly understood. The interpretation of lymphatic drug transport data is further complicated by variations in dosing excipients and dispersed states, study models, prandial (fed/fasted) states, intravenous dosing conditions and formulations used for the assessment of absolute bioavailability. The studies described in this thesis investigated various factors affecting the intestinal lymphatic transport and oral bioavailability assessment of highly lipophilic compounds using lymph-cannulated and non lymph-cannulated animals. These factors examined included subtle differences in lipophilicity and lipid solubility of chemically similar drug analogues, lipid and non-lipid based oral formulations, intravenous dosing states and dosing conditions. The impact of lymphatic drug delivery on systemic exposure, clearance and drug deposition was also examined in comparison with portal route of drug absorption in this thesis. Oral bioavailability of highly lipophilic analogues was significantly enhanced after administration in long chain lipid-based formulations via stimulation of intestinal lymphatic transport and significantly influenced by subtle differences in lipid solubility, however, not lipophilicity as indicated by log P. After delivery in lymph or the lipid-based emulsion, systemic clearance (Cl) and volume of distribution (Vd) of a highly lipophilic, lymphatically transported model drug, halofantrine (Hf) were significantly lower than when delivered in plasma or lipid-free co-solvent formulation. However, where drug and lipid entered the systemic circulation coincidentally, Cl and Vd were unaffected by the route of entry, but significantly altered by total plasma lipid levels. These findings suggest that a mismatch in plasma lipid levels after intravenous and oral administration may lead to differences in drug clearance and errors in bioavailability assessment. This thesis also investigated the influence of absorption route (lymphatics vs. blood) on drug pharmacokinetics and tissue distribution. Brain to blood ratios were found to be significantly lower after stimulation of intestinal lymphatic delivery suggesting that drug association with intestinal lymph lipoproteins might limit brain drug access. Lipophilic model compounds (DDT, Hf) and lipids were assessed following delivery to the systemic circulation in association with lymph lipoproteins or plasma, and were found to differ significantly. For DDT, 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 to the route of absorption may thus directly impact on pharmacokinetics and tissue distribution, whereas for Hf, factors which influence lymphatic transport may, by altering systemic lipoprotein concentrations, indirectly impact pharmacokinetics and tissue distribution. Ultimately, careful control of dosing conditions and thus the extent of lymphatic transport may be important in assuring reproducible efficacy and toxicity for lymphatically transported drugs.