**6. Future Perspective**

Growing evidence has demonstrated that diabetes often simultaneously affects transporters and enzymes in the intestine, liver and kidney. Moreover, these alterations are dependent on tissue and diabetic progression. For example, diabetes induced the expression of hepatic CYP3A, but downregulated the expression of intestinal CYP3A. In STZ/HFD-induced diabetic rats, 10-day diabetes decreased the expression of both intestinal and hepatic BCRP, but 22-day diabetes induced the expression of intestinal BCRP not hepatic BCRP protein [11]. Moreover, mRNA levels are often indexed as the expression of targets, but mRNA levels do not always reflect the protein expression and activity. For example, a report showed that diabetes induced a five-fold increase in the expression of renal Mdr1a mRNA in rats, but the expression of renal P-gp protein was unaltered [138]. Similarly, mRNA expression of BCRP in the liver of GK rats was increased by 20-fold, but the expression of BCRP protein and function (biliary excretion of rosuvastatin) was unchanged [19]. In contrast, diabetes decreased the level of hepatic MRP2 protein by 80% in rats without affecting the mRNA expression of MRP2 [22]. Similarly, no correlation between the mRNA level and activity (chlorzoxazone 6-hydroxylation activity) of CYP2E1 was also found in human liver [154]. All these indicate that data based on mRNA sometimes give the wrong conclusion. Clinical trials [66,68,73,74,131,132] have also demonstrated that many factors such as type of diabetes, diabetic progression, gender, age, therapy/effectiveness, diet/drinking habits, complications and co-medicines affect expressions and functions of CYP450s and transporters, which may partly explain contradictory effects of diabetes on expressions of CYP450/transporters and pharmacokinetics. Alterations in expressions and functions of transporters and CYP450s by diabetes are dependent on specific isoforms (CYP450s and transporters) and tissues. Moreover, physiological parameters such as blood flow rates in tissues are altered. All these results indicate that alterations in the disposition of drugs under diabetes should be attributed to the integrated effect of these factors. We thought that PBPK model could be used to accomplish the prediction of drug disposition under diabetic status. Furthermore, the PBPK model could separately illustrate individual contributions of each factor to drug disposition and their integrated effects.

**Author Contributions:** Both authors shared in the searching for publication, preparation and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by National Natural Science Foundation of China (No. 81573490)

**Conflicts of Interest:** The authors declare no conflict of interest.
