Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug.

The influence of liquid intake and a lipid-rich meal on the bioavailability of a lipophilic drug was investigated. Danazol was used as the model substance. In a randomized four-way crossover study eight healthy male volunteers received four different treatments with danazol at 2-week intervals following an overnight fast (one I.V. infusion and three oral treatments). The I.V. formulation contained 50mg danazol solubilized in 40% hydroxypropyl-beta-cyclodextrin. The oral treatments were a Standard treatment, a Standard + 800 ml water treatment and a Standard + lipid-rich meal treatment. The Standard oral treatment consisted of 200 ml water and one capsule containing 100mg danazol, three 500 mg paracetamol tablets and two 500 mg sulfasalazine tablets. Paracetamol and sulfasalazine were used as markers for gastric emptying and small intestinal transit times. Intake of danazol with a lipid-rich meal or extra 800 ml water increased the bioavailability by 400 and 55%, respectively. Gastric emptying times increased in the following order: Standard

In vivo in vitro correlations for a poorly soluble drug, danazol, using the flow-through dissolution method with biorelevant dissolution media.

The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Müllertz, A. 2005. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug, Eur. J. Pharm. Sci. 24, 297-303]. In the fasted state, the physiologically most relevant correlation with in vivo results was achieved with a medium containing 6.3 mM bile salts and 1.25 mM phospholipids (8 ml/min). A medium containing 18.8 mM bile salts, 3.75 mM phospholipids, 4.0 mM monoglycerides and 30 mM fatty acids (8 ml/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissolution method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium composition were important for the dissolution of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.