Physiologically based pharmacokinetic model of mechanism-based inhibition of theophylline/caffeine by enoxacin/ciprofloxacin

To characterize the mechanism-based inhibition of CYP1A2 activity by enoxacin (ENX) or ciprofloxacin (CPFX) and develop a physiologically based pharmacokinetic (PBPK) model to predict the interactions between theophylline (TP) or caffeine (CAF) and enoxacin or ciprofloxacin using in vitro study from phenacetin.CYP1A2 activity in pooled human hepatic microsomes was assessed using phenacetin O-deethylation following incubation with ENX or CPFX,respectively.A PBPK model characterizing mechanism-based inhibition was developed to clarify the interaction between TP or CAF and ENX or CPFX.The results showed that ENX and CPFX themselves were weakly reversible inhibitors of CYP1A2 in pooled human hepatic microsomes,but following pre-incubation with NADPH system and ENX or CPFX in pooled human hepatic microsomes,the inhibitory effects on phenacetin O-deethylation were significantly enhanced.The inhibition was NADPH-,pre-incubation time-,and ENX or CPFX concentration-dependent,characterizing mechanism-based inhibition.The developed PBPK model for characterizing mechanism-based inhibition was successful applied to predict the interaction between TP or CAF and ENX or CPFX.Enoxacin and ciprofloxacin are mechanism-based inhibitors of CYP1A2.The interactions between TP or CAF and ENX or CPFX may be predicted using PBPK model characterizing mechanism-based inhibition of CYP1A2 and in vitro study from phenacetin.