FK506 increases permeability in rat intestine by inhibiting mitochondrial function.
OBJECTIVE
Under normal physiological conditions, the intestine presents an adenosine triphosphate (ATP)-dependent barrier to luminal contents. Disruption of this barrier function can occur when cellular metabolism is compromised. This study examined the effects of FK506 on intestinal permeability and enterocyte metabolic function in Lewis rats.


METHODS
Rats were administered FK506 at a dose of 0.1, 0.5, or 2 mg/kg on alternate days for 6 weeks. Intestinal permeability was assessed by measuring urinary recovery of 99mTc-diethylenetriamine pentacetate, and electrophysiological conductance measurements were performed in Ussing chambers. Metabolic function was assessed in isolated enterocytes by measuring total ATP and CO2 release from [14C]pyruvate and [14C]glucose.


RESULTS
Rats treated with FK506 showed a dose-dependent reduction in weight gain as well as increased in vivo and in vitro intestinal permeability. There was no difference in plasma creatinine or urinary output. Changes in permeability correlated with reduced ATP levels and CO2 release because of diminished mitochondrial function. Lactate production, as a measure of glycolytic activity, was not altered by FK506.


CONCLUSIONS
In a dose-dependent manner, FK506 treatment in rats reduces weight gain, increases intestinal permeability, and decreases the ability of the small intestine to use glucose as an energy source.
Madsen
K L
KL
Division of Gastroenterology, University of Alberta, Edmonton, Canada.
Yanchar
N L
NL
Sigalet
D L
DL
Reigel
T
T
Fedorak
R N
RN
D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004594:Electrophysiology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007773:Lactates / Q000096:biosynthesis; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000009:adverse effects*; D016284:Technetium Tc 99m Pentetate / Q000493:pharmacokinetics; D015430:Weight Gain / Q000187:drug effects
D007773:Lactates; D002248:Carbon Monoxide; D000255:Adenosine Triphosphate; D016284:Technetium Tc 99m Pentetate; D016559:Tacrolimus