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.