Use of a dynamic in vitro lipolysis model to rationalize oral formulation development for poor water soluble drugs: correlation with in vivo data and the relationship to intra-enterocyte processes in rats.
OBJECTIVE
To examine the correlation between the in vitro solubilization process of lipophilic compounds from different lipid solutions and the corresponding in vivo oral bioavailability data. In particular, to assess the influence of intra-enterocyte processes (metabolism and lymphatic absorption) on this correlation.


METHODS
The dissolution of progesterone and vitamin D3 in long (LCT), medium (MCT) and short (SCT) chain triglyceride solutions were tested in a dynamic in vitro lipolysis model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. Vitamin D3 bioavailability was also examined following lymphatic transport blockage induced by cycloheximide (3 mg/kg).


RESULTS
The dynamic in vitro lipolysis experiments indicated a rank order of MCT > LCT > SCT for both progesterone and vitamin D3. The bioavailability of progesterone correlated with the in vitro data, despite its significant pre-systemic metabolism. For vitamin D3, an in vivo performance rank order of LCT > MCT > SCT was obtained. However, when the lymphatic transport was blocked the bioavailability of vitamin D3 correlated with in vitro data.


CONCLUSIONS
The in vitro lipolysis model is useful for optimization of oral lipid formulations even in the case of pre-systemic metabolism in the gut. However, when lymphatic transport is a significant route of absorption, the in vitro lipolysis data may not be predictive for actual in vivo absorption.
Dahan
Arik
A
Department of Pharmaceutics, School of Pharmacy Faculty of Medicine, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel.
Hoffman
Amnon
A
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002762:Cholecalciferol / Q000737:chemistry; D002914:Chylomicrons / Q000378:metabolism; D003513:Cycloheximide / Q000008:administration & dosage / Q000737:chemistry; D020895:Enterocytes / Q000502:physiology*; D006207:Half-Life; D008066:Lipolysis; D008208:Lymphatic System / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D011374:Progesterone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014280:Triglycerides
D002914:Chylomicrons; D011500:Protein Synthesis Inhibitors; D014280:Triglycerides; D002762:Cholecalciferol; D011374:Progesterone; D003513:Cycloheximide