Mechanism-based inhibition of CYP1A2 by antofloxacin, an 8-NH2 derivative of levofloxacin in rats

A recent focus was to investigate whether antofloxacin, an 8-NH2 derivative of levofloxacin, inhibited cytochrome P450 (CYP) 1A2 activity in rats. Phenacetin, the representative substrate of CYP1A2, was used as the model drug to evaluate the activity of CYP1A2. In an in vivo study, an oral single dose of antofloxacin (20mgkg ^-1) did not affect the pharmacokinetic behaviour of phenacetin, but a multidose (20mgkg ^-1 twice daily for 7.5 days) significantly increased phenacetin's area under the curve (AUC). In an in vitro study, only when pre-incubated with β-nicotinamide adenine dinucleotide phosphate, a reduced form (NADPH) system in rat liver microsomes, did antofloxacin inhibit phenacetin O-deethylation. The inhibition was NADPH-, pre-incubation time-, and antofloxacin concentration-dependent. A physiologically based pharmacokinetic model with mechanism-based inhibition was successfully developed for predicting the interaction between antofloxacin and phenacetin in vivo from the in vitro data. The simulated AUC was 1.4-fold of the control, which was near the observed value of 1.6-fold. From the results, it can be concluded that the inhibition of CYP1A2 by antofloxacin is mechanism-based.