Two‐ to three‐fold increase in blood tacrolimus (FK506) levels during diarrhea in liver‐transplanted children

Abstract

Background: The diagnosis and treatment of diarrhea in liver transplant recipients often pose a challenge owing to the variety of infectious and non‐infectious causes. However, diagnosis is principally focused on ruling out an infectious etiology. Tacrolimus, an immunosuppressive agent generally used after liver transplantation, is absorbed mainly from the duodenum through the upper jejunum. It can be assumed that metabolism of the drug will be influenced by diarrhea. Methods: Four liver transplant recipients who developed an episode of acute gastroenteritis. Infectious etiology was confirmed; trough tacrolimus levels were measured before, during and after gastroenteritis. Results: All patients presented a two‐ to three‐fold increase in blood tacrolimus levels after the onset of gastroenteritis. Conclusions: Until the role played by the intestine in the metabolism of tacrolimus is fully understood, it is prudent to recommend early dose reduction of tacrolimus and careful monitoring of trough levels during diarrheal disorders of any nature in pediatric liver‐transplanted patients.

A cluster of rotavirus enteritis in adult transplant recipients

“…Infection is the most common complication after solid organ transplantation. Diarrhea is a common side effect of immunosuppressive drugs such as MMF and sirolimus, but has also been associated with antibiotics [1,5–8]. In immunocompromised patients numerous microbes including viruses such as CMV and EBV as well as bacterial, protozoal and fungal pathogens may cause enteric infection [1].…”

“…Tacrolimus is a potent immunosuppressive drug frequently used in liver transplantation [5–8]. During diarrhea a significant increase in trough levels of TAC in pediatric transplant recipients has been reported [5].…”

“…During diarrhea levels of tacrolimus (TAC) may increase excessively [5]. This was observed specifically during RV‐associated diarrhea in pediatric transplant recipients [6–8]. For this reason careful monitoring of TAC levels during diarrhea is mandatory [5,6,8].…”

Epstein-Barr Virus—Associated Posttransplantation Lymphoproliferative Disorder With Tacrolimus Metabolism Deterioration in Infants After Living-Donor Liver Transplantation

“…A previous report showed 1.3-to 4.0-fold increases in the Tac trough level and decreased intestinal P-glycoprotein activity in the presence of diarrhea among liver or renal transplant recipients. [15][16][17][18] A higher Tac trough level can also cause diarrhea as an adverse event related to the administration of Tac and may lead to abnormally accelerated intestinal absorption of Tac. 19 Previous reports have shown that EBV can cause mild-to-severe hepatitis with characteristic portal and intrasinusoidal lymphocytic infiltration with apoptotic hepatocytes.…”

Impact of gastrointestinal‐related side effects on mycophenolate mofetil dosing and potential therapeutic strategies

“…While GI events such as diarrhea occur more frequently with tacrolimus than CsA in the absence of MPA (47–49), possibly because of a prokinetic effect of tacrolimus on the GI tract (50), the known pharmacokinetic interaction between MPA and tacrolimus that is not seen with CsA is also likely to contribute (51). It should also be borne in mind that diarrhea results in a significant rise in tacrolimus trough levels (52, 53), which in turn could exacerbate GI intolerance. In cases of persistent diarrhea with a corresponding marked elevation in tacrolimus blood concentrations, short‐term tacrolimus dose reductions may be appropriate, although the dose must of course be increased promptly if persistent diarrhea resolves (54, 55).…”