Figure 1.

DDI PBPK modeling overview. Whole-body PBPK models for ketoconazole and its metabolites were established and used to simulate the inhibitory effect of ketoconazole, which is substrate of CYP3A4, AADAC, UGT1A4, and P-gp. Its metabolite M1, which is formed by AADAC biotransformation, is metabolized by FMO3 to M2, which is metabolized via FMO3 as well. Both the parent compound and the metabolites concomitantly inhibit CYP3A4 and P-gp. CYP3A4-related DDIs were simulated with the CYP3A4 victim drugs alfentanil, alprazolam, midazolam, and triazolam. P-gp DDIs were simulated with the P-gp victim drug digoxin. Drawings by Servier (licensed under CC BY 3.0) [32]. AADAC: arylacetamide deacetylase, CYP3A4: cytochrome P450 3A4, FMO3: flavin-containing monooxygenase 3, M1: N-deacetylketoconazole, M2: N-deacetyl-N-hydroxyketoconazole, P-gp: P-glycoprotein, UGT1A4: uridine diphosphate glucuronosyltransferase 1A4.