The effect of tacrolimus (FK506) on intestinal barrier function and cellular energy production in humans

Background & Aims: The maintenance of the intestinal mucosal barrier may be energy dependent. Tacrolimus is a potent immunosuppressive drug that decreases mitochondrial adenosine triphosphate production and increases intestinal permeability in animals. Methods: Twelve liver graft recipients receiving tacrolimus, 9 healthy volunteers, and 5 liver graft recipients not receiving immunosuppression underwent a combined absorption-permeability-mitochondrial function test using 5 g lactulose, 1 g L-rhamnose, 0.5 g D-xylose, 0.2 g 3-o-methyl-D-glucose, 1 mg/kg 2-keto[1-(13)C]isocaproic acid ([(13)C]KICA), and 20 mg/kg L-leucine. The respiratory quotient and resting energy expenditure were measured by indirect calorimetry. Tacrolimus pharmacokinetic profiles and levels of endotoxin and IgM and IgG endotoxin core antibodies were determined. Results: Tacrolimus inhibited the decarboxylation of [(13)C]KICA, the resting energy expenditure, and the respiratory quotient in an exposure-dependent manner, suggesting an inhibition of mitochondrial respiration. Tacrolimus inhibited intestinal absorptive capacity in an exposure-dependent manner. Tacrolimus-treated patients had an increased intestinal permeability and significantly higher endotoxin levels compared with healthy volunteers. Conclusions: Tacrolimus inhibits cellular energy production in humans at clinically relevant doses. This is associated with an increased intestinal permeability, endotoxemia, and an impaired intestinal absorptive capacity.