Evaluation of drug-drug interaction between rosuvastatin and tacrolimus and the risk of hepatic injury in rats.

Multimorbidity, therapeutic complexity, and polypharmacy, which greatly increases the risk of drug-drug interactions (DDIs) and adverse medical outcomes, have become important and growing challenges in clinical practice. Statins are frequently prescribed to manage post-transplant dyslipidemia and reduce overall cardiovascular risk in solid organ transplant recipients. This study aimed to determine whether rosuvastatin has significant DDIs with tacrolimus (the first-line immunosuppressant) and to evaluate the risk of hepatotoxicity associated with concomitant therapy. We first studied whether a rat model could be established to assess the magnitude of rosuvastatin-tacrolimus DDI. The liver function index and histopathological examination were performed to investigate the characteristics of hepatotoxicity in the presence and absence of DDI. The clinical DDI potential between rosuvastatin and tacrolimus was also explored. Single-dose intravenous administration of tacrolimus did not significantly affect the area under the plasma concentration-time curve (AUC), clearance (CL), and volume of distribution at steady-state (V) of rosuvastatin in rats, despite a 96.7% increase in the rosuvastatin maximum plasma concentration (P = 0.024). Multiple doses of intravenous tacrolimus had no effect on the systemic disposition of rosuvastatin, but significantly increased aspartate transaminase (AST) by 42.6% (P = 0.043). Multiple doses of intravenous tacrolimus and rosuvastatin significantly altered the disposition of rosuvastatin, reducing alanine aminotransferase (ALT) and AST by 38.3% (P = 0.040) and 31.6% (P = 0.019), respectively. Histological evaluation of the liver specimens revealed patterns of drug-induced liver injury in rats. At clinically relevant doses, tacrolimus was predicted to be unable to cause pharmacokinetic interactions with rosuvastatin through basic models. The concomitant administration of tacrolimus and rosuvastatin has a minor impact on rosuvastatin pharmacokinetics; however, mild hepatotoxicity has been observed in rats.