Background: Intestinal transplantation (Itx) is a therapeutic option for patients with short gut syndrome and other end stage gastrointestinal disease states. Acute cellular rejection (ACR) is common within the first year of intestinal transplant (67%). During ACR, T cell infiltration, increased local pro-inflammatory cytokines, including IL-1beta, IL-2, IL-6, and TNF-alpha, and down regulation of the expression of messenger RNAs of CYP3A and Multi drug resistance 1 (MDR1) gene will occur. This is anticipated to inhibit CYP3A-mediated gut metabolism and transporter-mediated efflux of drugs via p-glycoprotein (P-gp). Pro-inflammatory release also damages the mucosal barrier, which increases intestinal permeability. However, it is not known how these physiological changes during ACR affect the pharmacokinetic parameters of absorption and bioavailability in enteral medications. The purpose of this study was to evaluate the impact of acute cellular rejection (ACR) on dose-normalized tacrolimus blood concentrations in intestinal transplant recipients.

Method: A retrospective, single-center, cohort study of adult intestinal transplant recipients experiencing acute cellular rejection from February 1998 to July 2013 was conducted. Primary outcome was change in dose-normalized tacrolimus concentrations. Secondary outcomes included differences in percent change of dose-normalized tacrolimus by rejection grade, treatment agent, time post-transplantation, and rejection episode. Serum creatinine and blood urea nitrogen levels were assessed for nephrotoxicity.  

Results: One hundred thirteen intestinal transplant recipients experienced 284 ACR episodes. Median dose-normalized concentrations were higher during ACR compared to before or after ACR (8.7 ng/mL/mg vs 3.1 ng/mL/mg, respectively p<0.001). Increases in absolute TAC levels were associated with increases in  SCr (p=0.004), BUN (p<0.001), and potassium (p<0.001) during ACR. These observations demonstrate increased systemic concentrations and toxicities with tacrolimus in ITx transplant patients during ACR.

Conclusions: Systemic availability of tacrolimus is increased during acute rejection of SBTx. Higher exposure to other enteral medications are expected during ACR in SBTx patients.