Cyclosporine NEORAL Oral Solution Novartis is an immunosuppr
Cyclosporine (NEORAL® Oral Solution, Novartis) is an immunosuppressant widely used in organ transplantation and many other clinical conditions . It undergoes extensive hepatic and intestinal biotransformation mainly via the metabolizing enzyme, CYP3A4 [, , , ]. Considering the narrow therapeutic index of cyclosporine, the change in drug bioavailability may result in serious consequences, either increased toxicity or therapeutic failure . Several reports indicated that CYP3A4 inhibitors or inducers can significantly change the bioavailability of cyclosporine .
Materials and methods
Discussion DDI is one of the main problems with serious clinical consequences in clinical settings. Several reports have highlighted the role of modulation of drug-metabolizing enzymes, especially CYP450 s, as a major mechanism involved in clinical DDIs [3,4,7]. The present study aimed to investigate the effect of dasatinib and nilotinib on the bioavailability of cyclosporine A in a rat model. Furthermore, we examined the effect of dasatinib on mRNA and protein vip receptor of the CYP3A2 enzyme in rat liver and intestine. Rats are frequently used as in vivo models for DDIs based on the inhibition/induction of CYP450 isoenzymes, although considerable variations were reported in the activity of CYP450 isoenzymes among different species. The activity of CYP450 isoenzymes in mice and male rats showed the most similarity to that in humans [, , , ]. However, studies reported a little effect of rifampicin on the metabolism of testosterone in rat hepatocytes, although dexamethasone showed a significant effect in the same study . TKIs are an important group of drugs that have recently emerged as effective oral anticancer therapy. However, due to their extensive interactions with CYP450 s and their chronic prescription pattern, TKIs are frequently involved in clinical DDIs. Dasatinib and nilotinib are among the TKIs approved by the US-FDA for the treatment of chronic myeloid leukemia. Their CYP3A4 mechanism-based inhibition has been reported in in vitro studies . In a healthy human, dasatinib increased the exposure of simvastatin, a CYP3A4 substrate . Another study showed an increased bioavailability of midazolam after single and repeated administration of nilotinib [2,4]. However, the exhaustive information on the in vivo impact of these TKIs on CYP3A4 and P-glycoprotein substrates is lacking. In particular, the impact of these TKIs on cyclosporine, which is a known CYP3A4 and P-glycoprotein substrate and undergoes extensive hepatic and intestinal metabolism, has not been reported [, , , ]. Moreover, altered bioavailability has been reported in instances of cyclosporine co-administration with drugs that modulate CYP3A4 isoenzyme activity [16,28,29]. In this study, the pretreatment with dasatinib for 8 consecutive days revealed an extraordinary finding regarding the impact of dasatinib on cyclosporine bioavailability. Pretreatment of rats with 16 mg/kg dasatinib markedly decreased the cyclosporine blood concentration (81.3%), as clearly demonstrated in Fig. 1. The pre-treatment with dasatinib (4 mg/kg) also significantly decreased the Cmax of cyclosporine (85.7%) (Fig. 1 and Table 1). The effect of nilotinib on cyclosporine blood levels was insignificant (Fig. 2, Table 2) although previous studies have reported an increase in the bioavailability of some CYP3A substrates when coadministered with nilotinib. Our results might explain the failure of cyclosporine to inhibit in vitro T cell proliferation when it was concomitantly used with dasatinib in experiments performed by Stephen et al. (2012), which showed a reversal of the inhibition of T cell proliferation by cyclosporine and an increase beyond that in untreated cells . On the other hand, dasatinib and some other TKIs have reported an in vitro mechanism-based inhibition of CYP3 A4; however, this effect is a substrate-dependent. For example, although gefitinib and erlotinib are CYP3A4 inhibitors, but they stimulated the metabolism of CYP3A substrates such as midazolam; however, the underlying mechanism remains unclear [, , ].The study showed the differential effect of TKIs on cyclosporine bioavailability, which clearly demonstrates the need for great caution when these drugs are co-administered with cyclosporine and other CYP3A4 substrates, particularly those with a narrow therapeutic index.