TARGETED LYMPHATIC TRANSPORT AND MODIFIED SYSTEMIC DISTRIBUTION OF CI-976, A LIPOPHILIC LIPID-REGULATOR DRUG, VIA A FORMULATION APPROACH

CI-976 is a poorly water soluble lipid regulator with good solubility in triglycerides and a high octanol:water partition coefficient. These physicochemical properties suggest significant lymphatic transport fo llowing gastrointestinal absorption. Studies were conducted to assess the relative contribution of lymphatic transport to total systemic bio availability. Following intraduodenal administration to conscious rats as either a 20% o/w emulsion prepared from a mixture of soybean and s afflower oils, or as an aqueous suspension, the percentage contributio n of lymphatic transport to bioavailability as reflected by CI-976 pla sma AUC was 43% for the emulsion and 57% for the suspension. However, the total quantity of CI-976 transported in lymph over 14 h, as a perc ent of dose administered, was 7-times greater for the emulsion as comp ared to the suspension. Tissue distribution studies using [C-14]CI-976 showed that, compared to the suspension, the emulsion delivery system resulted in 43% greater accumulation of intact CI-976 in the perirena l fat. Enhanced lymphatic transport is not necessarily reflected by a proportionally elevated plasma AUC, therefore plasma AUC alone may not be representative of total systemic bioavailability of drug.