Disposition of two highly permeable drugs in stomach and in upper small intestine of healthy adults after a standard high-calorie, high-fat meal.

OBJECTIVES: To quantify the presence of two model highly permeable drugs, paracetamol and danazol, in the upper gastrointestinal lumen under conditions simulating the situation after disintegration of immediate release dosage forms administered in bioavailability/bioequivalence studies in the fed state. To understand the drug transfer process from the antral contents through the upper small intestine using the luminal drug data. METHODS: 8 healthy male adult volunteers participated in a randomized, single dose, two-phase, crossover study. After evaluating the impact of homogenization on meal's viscosity and particle size, the meal, containing phenol red as non-absorbable marker, was administered to the antrum via the gastric lumen of a naso-gastro-intestinal tube. The drugs were administered in solution form (Phase I) and in suspension form (Phase II) with a glass of tap water to the antrum of the stomach, 30 min after the initiation of meal administration. Samples were aspirated from the antrum and the upper small intestine up to 4 hours post drug administration. RESULTS: Apparent concentrations in the aqueous contents of the antrum were higher than apparent concentrations in micellar contents of the upper small intestine for paracetamol; the opposite was observed for danazol. Based on total drug amount per volume data in contents of upper gastrointestinal lumen, the transfer of paracetamol (aqueous solution or suspension) and danazol (aqueous suspension) through the upper small intestine could be described as an apparent first-order process. Transfer of a long-chain triglyceride solution of danazol was highly variable. CONCLUSIONS: Concentrations in the aqueous/micellar phase of luminal contents and values of parameters controlling the transfer from bulk gastric contents through the upper small intestine, after a high-calorie, high-fat meal, were reported for first time for highly permeable drugs. Data are expected to enhance the development of biorelevant in vitro and physiologically based biopharmaceutics modelling methodologies.