Effect of Probiotics on Immunosuppressive Drug Pharmacokinetics: Interaction between <i>Bacillus subtilis</i> and Tacrolimus in Mice

The pharmacokinetics of drugs significantly affects their efficacy and adverse effects. Clarifying and predicting individual pharmacokinetic differences is crucial for the appropriate use of pharmaceuticals. Recent studies have suggested that the metabolic potential of intestinal bacteria may influence individual differences in pharmacokinetics. The consumption of probiotics, including supplements and fermented foods, has increased as a recent health trend. However, probiotics may also influence drug pharmacokinetics. In this study, we focused on the immunosuppressive drugs tacrolimus, everolimus, and cyclosporin A, which require careful dosing regimens, and investigated their interactions with microorganisms present in probiotics. Among the evaluated microorganisms, Bacillus subtilis exhibited a particularly strong drug degradation activity, with B. subtilis TO-A reducing the residual rates of tacrolimus and everolimus by 8 and 17%, respectively, in vitro. In a nonclinical pharmacokinetic trial, mice administered B. subtilis TO-A showed a significant reduction in the maximum blood concentration of tacrolimus. The concentration was 86.36 ± 63.61 ng/mL, much lower than that (212.8 ± 67.40 ng/mL) observed in the non-administered group. Based on these results, we can infer that orally ingested microorganisms can metabolize pharmaceuticals before reaching the small intestine, which is the primary site of absorption. These findings strongly suggest the need for caution when concurrently administering tacrolimus and probiotics in humans.