A physiologically based pharmacokinetic model characterizing mechanism-based inhibition of CYP1A2 for predicting theophylline/antofloxacin interaction in both rats and humans

Clinical studies have revealed that some fluoroquinolones may cause severe adverse effectswhen co-administered with substrates of CYP1A2. Our previous study showed antofloxacin (ATFX) wasresponsible for mechanism-based inhibition (MBI) of the metabolism of phenacetin in rats. In the clinicalsetting, ATFX is likely to be administrated with theophylline (TP), which is mainly metabolized by CYP1A2.The aim of the present study was to investigate the possible mechanism of TP/ATFX interaction. In vitrostudies showed that the inhibitory effect of ATFX on the formation of three TP metabolites depended onNADPH, the pre-inhibition time, and ATFX concentration, i.e., factors which characterize MBI. In vivostudies demonstrated that single-dose ATFX (20mg/kg) did not affect the pharmacokinetic behavior of TP,but multidose ATFX (20mg/kg b.i.d. for 7.5 days) significantly increased the AUC of TP, decreased theamount of three TP metabolites in urine, and suppressed hepatic microsomal activity. A physiologicallybased pharmacokinetic (PBPK) model characterizing MBI of the three TP metabolites was developed forpredicting TP/ATFX interaction in rats; this model was further extrapolated to humans. The predictedresults were in good agreement with observed data. All the results indicated that ATFX was responsiblefor MBI of the metabolism of TP, and the PBPK model characterizing MBI may give good prediction ofTP/ATFX interaction.