PURPOSE: The study was designed to evaluate the effect of delayed release (DR) on absorption and bioavailability of intestinally metabolized drugs after oral dosing, using the HMG-CoA reductase inhibitor simvastatin, a CYP3A substrate, as a model drug. MATERIALS AND METHODS: To target drug release and to assess regional gastrointestinal absorption of the CYP 3A substrate simvastatin from the distal parts of the intestine, delayed release film coated tableted oral dosage forms were developed. Simvastatin delayed release tablet, simvastatin immediate release capsule and simvastatin immediate release tablet Zocor were administered as single doses (20 mg) to fasting healthy volunteers in a crossover design. RESULTS:Simvastatin bioavailability was increased by a factor of three, as compared to the reference formulation Zocor. The overall metabolite levels from the immediate release capsules tended to be higher throughout the period studied than the metabolite levels following administration of Zocor and simvastatin delayed release dosage form. CONCLUSIONS: The interplay between gastrointestinal physiology (lower CYP 3A expression in the distal ileum and the colon) and formulation design (zero-order controlled release after a predetermined lag-time) resulted in successful absorption and bioavailability improvement and represent a viable strategy to reduce the dose of CYP 3A drugs.
RCT Entities:
PURPOSE: The study was designed to evaluate the effect of delayed release (DR) on absorption and bioavailability of intestinally metabolized drugs after oral dosing, using the HMG-CoA reductase inhibitor simvastatin, a CYP3A substrate, as a model drug. MATERIALS AND METHODS: To target drug release and to assess regional gastrointestinal absorption of the CYP 3A substrate simvastatin from the distal parts of the intestine, delayed release film coated tableted oral dosage forms were developed. Simvastatin delayed release tablet, simvastatin immediate release capsule and simvastatin immediate release tablet Zocor were administered as single doses (20 mg) to fasting healthy volunteers in a crossover design. RESULTS:Simvastatin bioavailability was increased by a factor of three, as compared to the reference formulation Zocor. The overall metabolite levels from the immediate release capsules tended to be higher throughout the period studied than the metabolite levels following administration of Zocor and simvastatin delayed release dosage form. CONCLUSIONS: The interplay between gastrointestinal physiology (lower CYP 3A expression in the distal ileum and the colon) and formulation design (zero-order controlled release after a predetermined lag-time) resulted in successful absorption and bioavailability improvement and represent a viable strategy to reduce the dose of CYP 3A drugs.
Authors: Thomayant Prueksaritanont; Raju Subramanian; Xiaojun Fang; Bennett Ma; Yue Qiu; Jiunn H Lin; Paul G Pearson; Thomas A Baillie Journal: Drug Metab Dispos Date: 2002-05 Impact factor: 3.922
Authors: Vipul Yadav; Yang Mai; Laura E McCoubrey; Yasufumi Wada; Motoyasu Tomioka; Satofumi Kawata; Shrikant Charde; Abdul W Basit Journal: Biomedicines Date: 2021-05-20
Authors: Juliane Fjelrad Christfort; Antonio José Guillot; Ana Melero; Lasse Højlund Eklund Thamdrup; Teresa M Garrigues; Anja Boisen; Kinga Zór; Line Hagner Nielsen Journal: Pharmaceutics Date: 2020-04-14 Impact factor: 6.321