THE EFFECT OF TACROLIMUS (FK506) ON INTESTINAL BARRIER FUNCTION AND CELLULAR-ENERGY PRODUCTION IN HUMANS

Background & Aims: The maintenance of the intestinal mucosal barrier m ay be energy dependent. Tacrolimus is a potent immunosuppressive drug that decreases mitochondrial adenosine triphosphate production and inc reases intestinal permeability in animals. Methods: Twelve liver graft recipients receiving tacrolimus, 9 healthy volunteers, and 5 liver gr aft recipients not receiving immunosuppression underwent a combined ab sorption-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-C-13]isocaproic acid ([C-13]KICA), and 20 mg/kg L-leucine. The respiratory quotient and resting energy expenditure were measured by indirect calorimetry. Tacrolimus pharmacokinetic profiles and levels o f endotoxin and IgM and IgG endotoxin core antibodies were determined. Results: Tacrolimus inhibited the decarboxylation of [C-13]KICA, the resting energy expenditure, and the respiratory quotient in an exposur e-dependent manner, suggesting an inhibition of mitochondrial respirat ion. Tacrolimus inhibited intestinal absorptive capacity in an exposur e-dependent manner. Tacrolimus-treated patients had an increased intes tinal permeability and significantly higher endotoxin levels compared with healthy volunteers. Conclusions: Tacrolimus inhibits cellular ene rgy production in humans at clinically relevant doses. This is associa ted with an increased intestinal permeability, endotoxemia, and an imp aired intestinal absorptive capacity.