Evaluation of pharmacokinetic interactions between bicyclol and co-administered drugs in rat and human liver microsomes in vitro and in rats in vivo

1. Bicyclol is a new synthetic anti-hepatitic drug and primarily metabolized by CYP3A. The aim of this study was to evaluate the pharmacokinetic interactions between bicyclol and co-administered drugs including metformin, pioglitazone, atorvastatin, fenofibrate, Cyclosporin A (CsA), and tacrolimus in rat and human liver microsomes (RLMs/HLMs) in vitro and in rats in vivo.

2. The depletion rate of bicyclol in RLMs was significantly inhibited by 44.8% and 35.5% after preincubation with pioglitazone and fenofibrate while the metabolite formation rate of bicyclol in HLMs was inhibited by 26.1% and 23.9% after preincubation and coincubation with tacrolimus, and by 20.2% after preincubation with CsA. Conversely, preincubation and coincubation with bicyclol significantly inhibited the depletion rate of pioglitazone in RLMs by 34.1% and 27.1%, respectively, and the formation rate of para- and ortho-hydroxy atorvastatin in RLMs and HLMs by 20.6–36.2%. There were no significant pharmacokinetic interactions between bicyclol and pioglitazone in rats after a single or multiple oral treatment.

3. As the selected inhibitory drug concentrations in vitro were significantly higher than those in clinical settings and the maximum inhibition rate did not exceed 50%, the clinically significant interaction between bicyclol and these co-administered drugs in humans is predicted less likely to happen.