Lymphatic uptake of MK-386, a sterol 5α-reductase inhibitor, from aqueous and lipid formulations

4,7-β-Dimethyl-4-aza-5α-cholestan-3-one (MK-386) is a specific inhibitor of type-1 5α-reductase, with over 104-fold greater solubility in lipid-type vehicles than in water. The absorption of orally administered MK-386 was investigated with three formulations to test the possibility that formulation can influence the absorption by altering the relative lymph/blood partitioning of MK-386. Drug concentrations in mesenteric lymph or in portal plasma were determined after administration of a 5 mg/kg dose in aqueous suspension, a mono-diglyceride/polysorbate 80 (MDG/PS80) vehicle or a soybean oil solution to conscious rats. Lymph volume collected over a 6 h period was in the order aqueous suspension>MDG/PS 80>soybean oil-dosed animals. Total mass of MK-386 collected in lymph also followed this trend. MK-386 radioactivity equivalents from all formulations were as much as 80-fold greater in lymph compared with portal plasma, and radioactivity was exclusively associated with parent drug in lymph. Traces of metabolites, but virtually no MK-386, were detected in portal plasma. Distribution of MK-386 into lymph was insignificant after intravenous administration. The results demonstrate that systemic availability of orally administered MK-386 was due to lymphatic, not portal blood transport, and the rate of transport determined in this model was influenced by formulation.