Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea

Abstract

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (±50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.

Pharmacogenetics in immunosuppressants: impact on dose requirement of calcineurin inhibitors in renal and liver pediatric transplant recipients

“…Differential gene expression of CYP3A and P-gp may explain the large interindividual variability of drug response [11]. Intestinal inflammation, manifest by diarrhea, increases the oral bioavailability of TAC, possibly through disruption of Pgp barrier [12]. Moreover, inhibition of drug-metabolizing enzymes, as well as transporters, is now recognized as the likely mechanism accounting for many drug-drug interactions, because transporters and CYP enzymes often share overlapping tissue expression and substrate capacities [13].…”

Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation

“…Furthermore, in situations of inflammation, ischemiareperfusion injury, diarrhea and shock, Pgp expression in the gut wall may be reduced leading to decreased Pgp levels and an increase in whole blood tacrolimus trough concentrations up to 100% (17,19,25,62,63). Pgp levels generally normalize within 48 h after the insult (17,19,63).…”

Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence

“…as well as genetic polymorphisms in CYP3A5 enzymes (discussed below). Moreover, certain conditions such as diarrhea affect the activity of those enzymes and influence the levels of CNIs, particularly TAC [25]. In order to prevent their side effects, the CNI dose is typically adjusted in the context of diarrhea.…”