Felodipine (FLD), a calcium channel antagonist, is commonly prescribed for the treatment of hypertension
either with Metoprolol (MET) or Ramipril (RAM) in two different drug combinations. FLD has high
plasma protein binding ability affecting its extraction recoveries from plasma samples. Hence, a specific
ultrasound assisted dispersive liquid-liquid microextraction (UA-DLLME) method coupled with HPLC
using photodiode array detector was developed and validated for the simultaneous determination of
FLD, MET and RAM in rat plasma after oral administration of these combinations. The factors affecting
UA-DLLME were carefully optimized. In this study, UA-DLLME method could provide simple and efficient
plasma extraction procedures with superior recovery results. Under optimum condition, all target drugs
were separated within 13 min. The validation procedures was carried out in agreement with US-FDA
guidelines and shown to be suitable for anticipated purposes. Linear calibration ranges were obtained
in the range 0.05–2.0mgmL−1 for FLD and MET and 0.1–2.0mgmL−1 for RAM with detection limits of
0.013–0.031mgmL−1 for all the studied drug combinations. The%RSD for inter-day and intra-day precisions
was in range of 0.63–3.85% and the accuracy results were in the range of 92.13–100.5%. The
validated UA-DLLME-HPLC method was successfully applied for the bioavailability studies of FLD, MET
and RAM. The pharmacokinetic parameters were calculated for all the investigated drugs in rats after
single-dose administrations of two different drug combinations. Although FLD was bioequivalent in the
two formulations, a small increase in plasma levels of MET and RAM was found in the presence of FLD.