Aim This study was aimed at evaluating the impact of phytochemicals of Aframomum melegueta (Alligator pepper; AM) seeds on the bioavailability of acetaminophen (N-acetyl-p-aminophenol; APAP) and amlodipine. Methods The everted intestinal sac model was used to assess the transfer of Acetaminophen and amlodipine across the GIT wall. A portion of the GIT was excised, everted, filled with physiological solution with both ends ligated to make a closed loop, and immersed in a beaker containing a concentration of the test drug either alone or in the presence of AM seed extract (AMSE). After a period of time to achieve transfer equilibrium, the everted tissues were removed, blotted dry on an absorbent paper and drained into a test-tube. The concentration of the test drug was determined in these serosal fluids to assess transfer efficiency. Results The seed extract severely inhibited the intestinal transfer of acetaminophen by as much as 82.4% while amlodipine transfer was enhanced up to 94.5%. Serosal concentration of acetaminophen in the absence and presence of AMSE were 7.62 ± 0.95 µg ml-1 and 1.34 ± 0.96 µg ml-1 (P<0.001), while that for amlodipine were 2.54 ±1.03 µg ml-1 and 4.94 ± 0.739 µg ml-1 respectively.. Conclusion The depression of APAP transfer was suggested to be as a result of chemical interaction with nitric oxide produced by the interaction of the phytoestrogens in the extract on GPCR-bound estrogen receptor. This type of interaction may have serious health consequences.