Effect of supersaturation on absorption of indomethacin and tadalafil in a single pass intestinal perfusion rat model, in the absence and presence of a precipitation inhibitor
Abstract
The effect of the degree of supersaturation (DS) on absorption of the model drugs indomethacin and tadalafil was elucidated in a single-pass intestinal perfusion (SPIP) model in rats. In addition, the performance of the precipitation inhibitor (PI) hydroxypropylmethylcellulose (HPMC) was evaluated when added at a concentration of 0.1% (w/v) to fasted state simulated intestinal fluid (FaSSIF and FaSSIFHPMC) used as perfusion medium. A supersaturated state was created by a solvent shift method where indomethacin or tadalafil dissolved in dimethyl sulfoxide (DMSO) were administered to a segment of the small intestine, which subsequently was perfused with FaSSIF or FaSSIFHPMC. The perfusate was collected for 60 min, and for one group of rats dosed with 30 mg tadalafil, for 120 min. Blood samples were drawn every 15 min. The solubility of indomethacin and tadalafil in the perfusate was determined. The DS of each drug in the perfusate was calculated by dividing the concentration in the perfusate at selected time points with the solubility. The DS was above one for all timepoints for both drugs, thus showing supersaturation during the time of perfusion. For indomethacin, no improvement of the DS was seen when perfusing with FaSSIFHPMC, compared to FaSSIF. For tadalafil, a higher DS was achieved when perfusing with FaSSIFHPMC compared to FaSSIF. Perfusing the drugs with FaSSIFHPMC resulted in a significantly lower area under the curve (AUC0-60 min) for plasma concentrations of…
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