title: A physiologically based pharmacokinetic model characterizing mechanism-based inhibition of CYP1A2 for predicting theophylline/antofloxacin interaction in both rats and humans.
abstract: Clinical studies have revealed that some fluoroquinolones may cause severe adverse effects when co-administered with substrates of CYP1A2. Our previous study showed antofloxacin (ATFX) was responsible for mechanism-based inhibition (MBI) of the metabolism of phenacetin in rats. In the clinical setting, 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 vitro studies showed that the inhibitory effect of ATFX on the formation of three TP metabolites depended on NADPH, the pre-inhibition time, and ATFX concentration, i.e., factors which characterize MBI. In vivo studies demonstrated that single-dose ATFX (20 mg/kg) did not affect the pharmacokinetic behavior of TP, but multidose ATFX (20 mg/kg b.i.d. for 7.5 days) significantly increased the AUC of TP, decreased the amount of three TP metabolites in urine, and suppressed hepatic microsomal activity. A physiologically based pharmacokinetic (PBPK) model characterizing MBI of the three TP metabolites was developed for predicting TP/ATFX interaction in rats; this model was further extrapolated to humans. The predicted results were in good agreement with observed data. All the results indicated that ATFX was responsible for MBI of the metabolism of TP, and the PBPK model characterizing MBI may give good prediction of TP/ATFX interaction.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Pan
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004347:Drug Interactions; D024841:Fluoroquinolones / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D023421:Models, Animal; D008962:Models, Theoretical; D015242:Ofloxacin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013806:Theophylline / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D024841:Fluoroquinolones; D010726:Phosphodiesterase Inhibitors; C522674:antofloxacin; D015242:Ofloxacin; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2