Overall the evidence and the results from in vivo studies
Overall, the evidence and the results from in vivo studies clearly indicate that cyclosporine biotransformation can be induced by dasatinib co-administration through induction of CYP3A expression. However, further studies are needed to explore the role of P-gp modulation in DDIs.
Conclusion In vivo pharmacokinetic studies showed that dasatinib monohydrate pretreatment significantly decreased the blood level of CsA in rats, which was most probably due to the induction of CYP3A2 isoenzymes. The nilotinib pre-treatment had no significant effects on cyclosporine pharmacokinetics in rats.
Role of the funding source
Conflict of interest
Introduction Retinol (vitamin A) is an essential fat-soluble vitamin which is contained in yellow–orange and green leafy vegetables in the form of retinol or as the precursor, β-carotene. It can also be purchased over-the-counter as a dietary supplement. Retinol is essential for growth, differentiation and maintenance of epithelial tissue, bone remodelling, and for proper function of both the visual and reproductive systems (Lotan, 1980). Pharmacological doses of vitamin A and other retinoids have been used clinically for their therapeutic activity in the treatment of dermatological disorders (Bollag, 1983), and as adjuvants in cancer chemotherapy (Newton and Sporn, 1979, Moon et al., 1997). Additionally, individuals commonly use dietary supplementation of retinol for either self-treatment or for the prevention of non-specific illness such as the common cold. Therefore, individuals may ingest large quantities of retinol for a variety of reasons. Clinical data on the risk of developing significant liver disease from chronic ingestion of excess amounts of retinol has shown conflicting results (Krause, 1865, Minuk et al., 1988). Therefore, the risk of developing hepatotoxicity associated with excess consumption of retinol remains uncertain. The metabolism of retinol involves a variety of cytochrome P450 (CYP450) isoforms. Rat CYP2B1 and CYP2C7, and human CYP2C8 have demonstrated an ability to metabolise retinol and retinoic ppar pathway to more polar products (Leo et al., 1984, Leo et al., 1989, Leo and Lieber, 1985). In the rabbit, CYP1A2 and CYP3A6 catalyse the conversion of retinal to retinoic acid (Roberts et al., 1991). Recently, CYP26 has been identified in mouse and human liver, and in the adult liver its transcriptional expression is induced by retinoic acid (Ray et al., 1997, Haque et al., 1998). In addition, the modulation of CYP450 activities in retinol-deficient and supplemented animals has been investigated by numerous groups, but the results are quite variable. Initially, Miranda et al. (1979) demonstrated that following 7 weeks on a retinol-deficient diet, rabbits exhibited a decreased catalytic activity of CYP2E1 and CYP3A. Siddik et al. (1980) demonstrated a significant decrease in the total hepatic CYP450 content following 8 weeks of retinol deficiency in rats. Other studies have also shown that levels of CYP2C7 may be regulated by retinoic acid concentrations. Cultured rat hepatocytes maintained in a vitamin A-deficient environment showed decreased expression of CYP2C7, but the expression of CYP2C7 levels returned to normal after retinoic acid administration (Westin et al., 1997). Using retinol-supplemented guinea pigs, Miranda et al. (1981) showed an increase in CYP2B and CYP2E1 activity. Alternatively, retinol supplementation in rabbits produced an increase in CYP3A activity with no change in CYP2E1 (Miranda and Chhabra, 1981). Furthermore, Murray et al. (1991) demonstrated a wide range of effects on a number of CYP450 isoforms including strong evidence for an increase in rat CYP3A catalytic activity and polypeptide levels. These studies provide evidence that in a variety of species the activities of the CYP450 isoforms are closely linked to the retinoid status of the animal. However, none of these studies was conducted with mice. Our previous work has shown that 3 days of retinol administration (75 mg/kg/day) does not alter the catalytic activity or polypeptide levels of CYP2E1 in the male Swiss Webster mouse (Inder et al., 1999). Therefore, there is preliminary evidence to suggest that retinol-induced changes in CYP450 isozymes are different between the rat and mouse.