**5. Application of PBPK to Transporter-Enzyme Interplay**

The above statements demonstrated that diabetes may simultaneously affect functions and expressions of transporters and enzymes in the intestine, liver and kidney. Their contributions to the disposition of drugs are often opposite. Moreover, some physiological parameters such as blood flow rates, intestinal transit and the free fraction of drug in plasma are often altered. Thus, the effects of diabetes on pharmacokinetics of drugs should be the integrated effects of these alterations, which may be accomplished using PBPK.
