Idiosyncratic drugs effects on MDR1 activity

Effect of idiosyncratic drugs on the transport activity of MDR1 in HepG2 cells in the presence and absence of an inflammatory context. In order to evaluate the implication of MDR1 in drug induced idiosyncratic hepatotoxicity we have studied the effect of four idiosyncratic drugs on the efflux activity of MDR1 in presence and absence of LPS and TNF-?.
Conclusion:
To our knowledge no previous studies demonstrated a link between nefazodone and MDR1, however our results showed that this drug possesses a potent inhibitory potential on MDR1 probably through a structure specific interaction with this transporter as is the case with BSEP. It is noteworthy that the inhibitory potential of nefazodone, telithromycin and even verapamil proved to be reversible as it was noticeably lost within an inflammatory context; probably due to a TNF-α-stimulated induction of MDR1 protein expression and functionality
Notes:
We have chosen specifically LPS and TNF-? to induce inflammation for two main reasons: first, in order to mimic the in vivo situation of previously validated animal models in which the co-administration of minimal doses of LPS with idiosyncratic drugs better revealed their potential hepatotoxicity; second, in order to elucidate any implication of MDR1 in inflammation associated drug induced liver toxicity since the LPS stimulated release of TNF-? is known to modulate hepatic drug transporters expression and activity Nile Red fluorescent nanoparticles