A Physiologically Based Pharmacokinetic Model Characterizing Mechanism-based Inhibition of CYP1A2 for Predicting Theophylline/Antofloxacin Interaction in both Rats and Humans.
Summary of "A Physiologically Based Pharmacokinetic Model Characterizing Mechanism-based Inhibition of CYP1A2 for Predicting Theophylline/Antofloxacin Interaction in both Rats and Humans."
Clinical studies revealed that some fluoroquinolones may cause severe adverse effects when co-administered with substrates of CYP1A2. Our previous study showed antofloxacin (ATFX) mechanism-basely inhibited the metabolism of phenacetin in rats. In clinic, 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 inhibitory effect of ATFX on formation of three TP metabolites depended on NADPH, pre-inhibition time and ATFX concentration, which characterized mechanism-based inhibition (MBI). In vivo studies demonstrated that single dose of ATFX (20 mg/kg) did not affect pharmacokinetic behavior of TP, but multidose of ATFX (20 mg/kg b.i.d. for 7.5 days) significantly increased AUC of TP, decreased the amount of three TP metabolites in urine and suppressed the hepatic microsomal activity. A physiologically based pharmacokinetic (PBPK) model characterizing MBI of three TP metabolites was developed for predicting TP/ATFX interaction in rats and further extrapolated to humans. The predicated results were in good agreement with observed data. All the results indicated that ATFX mechanism-basely inhibited the metabolism of TP and the PBPK model characterizing MBI may give good prediction of TP/ATFX interaction.
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University.
This article was published in the following journal.
Name: Drug metabolism and pharmacokinetics
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