Intravenous Dosing Conditions May Affect Systemic Clearance for Highly Lipophilic Drugs: Implications for Lymphatic Transport and Absolute Bioavailability Studies

ABSTRACT:The clearance (Cl) and volume of distribution (Vss) of a lipophilic, lymphatically transported drug, halofantrine (Hf) have been evaluated after intravenous delivery to the systemic circulation in ex vivo lymph and plasma, and compared with the data obtained after administration of a lipid-based emulsion and a lipid-free cosolvent formulation. Systemic Cl and Vss were significantly lower (approximately twofold) after delivery of Hf in lymph or the emulsion when compared with the administration in plasma or the cosolvent formulation. Preadministration of drug-free lymph, immediately before administration of drug in plasma, however, resulted in plasma profiles consistent with that obtained after administration of drug in lymph/emulsion. Where drug and lipid entered the systemic circulation coincidentally, systemic Cl of Hf, therefore, appeared to be relatively unaffected by the route of entry to the systemic circulation (i.e. via the lymph or the blood), but more significantly altered by total plasma lipid levels. Because temporal changes to plasma lipid levels occur as a result of the absorption of formulation or food-derived lipids and the infusion of intravenous lipid emulsions, the current data suggest that a mismatch in plasma lipid levels after intravenous and oral administrations may lead to differences in drug Cl and errors in bioavailability assessment. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association