Biorelevant In Vitro Dissolution Testing to Predict In Vivo Absorption of Furosemide after Oral Administration

Laura Magallanes, Nikoletta Fotaki, Virginia Bertola, Anna Barindelli, Marta Vazquez, Pietro Fagiolino

Research output: Contribution to conferenceAbstract

Abstract

Purpose To predict the in vivo dissolution profiles of Furosemide under different oral administration conditions and in different sexes based on biorelevant in vitro dissolution testing. Methods In vitro dissolution testing was performed with USP IV apparatus (flow-through cell apparatus), in order to simulate the transit of Furosemide tablets along the gastrointestinal tract (stomach and proximal gut) under fasted (in men and in women). In order to simulate the in vivo dissolution under fasted conditions in men, the dissolution studies were carried out in Fasted State Simulated Gastric Fluid (FaSSGF pH 1.6) for 60 min at a flow rate of 8 mL/min with sequential change to Fasted State Simulated Intestinal Fluid (FaSSIF pH 6.5) at a flow rate of 4 mL/min for 180 min. Two furosemide formulations from the Uruguayan market were tested: Lasix® (Reference) and Furosemide EFA (generic brand, Test). In order to compare the performance of furosemide’s dissolution between men and women, the gastrointestinal tract of women was simulated in vitro by adjusting the pH of FaSSGF to 2.5 (higher pH than in men), the flow-rate to 6 mL/min (lower contractile strength) and the duration of dissolution testing in the simulated gastric fluid to 90 min (longer gastric emptying in women compared to men). In addition, Lasix® (Reference) and Furosemide EFA (generic brand, Test) were tested with the USP IV apparatus in acetate buffer (pH 4.6) at a flow rate of 16 mL/min. An in vivo study, comparing the Lasix® (Reference) and Furosemide EFA (generic brand, Test) formulations, was performed under fasted state conditions in six healthy volunteers, three males and three females. Results Under fasted state conditions, in vitro dissolution of furosemide from the Furosemide EFA formulation was faster than the dissolution of furosemide from the Lasix® formulation in FaSSGF and dissolution profiles equaled in shape and reached the same amount dissolved 30 min after the media change. Either throughout the time that both formulations were tested in FaSSGF or when they were tested in the acetate buffer (pH 4.6), the Test formulation showed faster dissolution rate than the Reference formulation. Comparing the sexes, in the gastric phase a higher dissolution rate was observed in the men simulated conditions. From the in vivo study, bioavailability of furosemide was similar from both formulations in men, and slightly higher after Furosemide EFA administration in women in the fasted state, which correlates with the biorelevant in vitro dissolution testing with the sequential media change. A higher bioavailability of furosemide was observed in men than in women for both formulations. Sex-related difference in furosemide absorption correlates with the biorelevant in vitro dissolution results in terms of the absorption rate but not in terms of the amount absorbed. The biorelevant in vitro dissolution results predict the in vivo dissolution performance of furosemide. Towards the prediction of furosemide’s bioavailability it should be borne in mind that women due to their higher intestinal pH have a shorter absorption window in the upper part of the small intestine than men, and therefore a lower capacity to allow the non-ionized molecule to cross through the enterocytes. Conclusion Biorelevant in vitro dissolution tests with the USP IV apparatus are useful to predict the in vivo dissolution profiles of furosemide, and therefore its bioavailability. To predict the sex-related difference of the in vivo absorption of furosemide it was necessary to take into account the length of the absorption window that each sex have, in accordance with their intestinal pH.
Original languageEnglish
Publication statusPublished - 2015
EventAAPS Annual Meeting, 2015 - Orlando, USA United States
Duration: 25 Oct 201529 Oct 2015

Conference

ConferenceAAPS Annual Meeting, 2015
CountryUSA United States
CityOrlando
Period25/10/1529/10/15

Fingerprint Dive into the research topics of 'Biorelevant In Vitro Dissolution Testing to Predict In Vivo Absorption of Furosemide after Oral Administration'. Together they form a unique fingerprint.

Cite this