2.6 Evaluation of drug–drug interaction
A DDI evaluation experiment using the MO–MPS was carried out using CPT-11 and either simvastatin (SV, S0509, Tokyo Chemical Industry Co., Ltd., Japan), a lipid-lowering drug, or ritonavir (RTV, R0116, Tokyo Chemical Industry Co., Ltd., Japan), an anti-HIV drug, to effect metabolic functions change on the MO–MPS. The metabolism of CPT-11 to SN-38 would be decreased by the concomitant administration of SV, which is an inhibitor of carboxylesterase2 (CES2).(Shen et al., (2019)) We expect that the concomitant administration of CPT-11 and RTV, which is an inhibitor of cytochrome P450 3A4 (CYP3A4), would not affect the amount of SN-38 in the MO–MPS because CYP3A4 expression on HepG2 is quite low.(Huch et al., (2015)) CPT-11 concentration was 15 µM, whereas SV concentration was 1 µM, which makes CES2 expression to be 50%.(Fukami et al., (2010)) Because RTV concentration was 10 µM, the CYP3A4 expression of microsomes from the human liver becomes 5%.(Eagling et al., (1997)) The culture medium in the MO–MPS was exchanged every 24 h. After 72 h, cell densities were observed as previously mentioned. The effects of DDI on pharmacokinetics were evaluated by comparing the predicted cell density of the PK–PD model with that of the experimental results.