LYMPHATIC UPTAKE OF MK-386, A STEROL 5-ALPHA-REDUCTASE INHIBITOR, FROM AQUEOUS AND LIPID FORMULATIONS

4,7-beta-Dimethyl-4-aza-5 alpha-cholestan-3-one (MK-386) is a specific inhibitor of type-1 5 alpha-reductase, with over 10(4)-fold greater s olubility in lipid-type vehicles than in water. The absorption of oral ly administered MK-386 was investigated with three formulations to tes t the possibility that formulation can influence the absorption by alt ering the relative lymph/blood partitioning of MK-386. Drug concentrat ions in mesenteric lymph or in portal plasma were determined after adm inistration of a 5 mg/kg dose in aqueous suspension, a mono-diglycerid e/polysorbate 80 (MDG/PS80) vehicle or a soybean oil solution to consc ious rats. Lymph volume collected over a 6 h period was in the order a queous suspension > MDG/PS 80 > soybean oil-dosed animals. Total mass of MK-386 collected in lymph also followed this trend. MK-386 radioact ivity equivalents from all formulations were as much as 80-fold greate r in lymph compared with portal plasma, and radioactivity was exclusiv ely associated with parent drug in lymph. Traces of metabolites, but v irtually no MK-386, were detected in portal plasma. Distribution of MK -386 into lymph was insignificant after intravenous administration. Th e results demonstrate that systemic availability of orally administere d MK-386 was due to lymphatic, not portal blood transport, and the rat e of transport determined in this model was influenced by formulation. (C) 1998 Elsevier Science B.V. All rights reserved.