Role of Immune Modulators in Drug‐drug Interaction between Irinotecan and Taxol

Abstract

Drug-drug interaction (DDIs) is one of the major contributors to adverse drug reaction. Alterations of drug metabolizing enzymes (DMEs) by a drug can lead to changes in metabolism of other co-administrated drugs, which can in turn cause DDIs. Inflammation-mediated impairment of DMEs has been known to occur, however, the molecular mechanism is still not fully known. One of the primary mediators of inflammatory responses in the body are the Toll-like receptors (TLRs) and represents the first line of host defense against pathogens. So far 13 TLRs have been identified in mammals. We have previously shown activation of TLR2 and TLR4 leads to down-regulation of expression and activity of DMEs during inflammation, thus they may have a role in DDIs. In Phase I study of irinotecan and taxol combination therapy for advanced non-small cell lung cancer, preceding taxol treatment increased the levels of both irinotecan and its active metabolite, SN-38. Interestingly, we found that taxol induced the enzymes; Ugt1a1and Cyp 3a11 involved in irinotecan metabolism in TLR4 dependent manner. Therefore, we hypothesize that taxol will alter pharmacokinetics of irinotecan and SN-38 by regulating expression of Ugt1a1 & Cyp3a11 in TLR4-dependent manner. Taxol significantly induced expression of Cyp3a11 (~600fold) and Ugt1a1 (~4 fold) in TLR4WT hepatocytes whereas the induction was attenuated in TLR4 mutant. This TLR4 dependent induction of Ugt1a1 & Cyp3a11 by taxol resulted in higher levels of SN-38G by ~2 fold at 24h when treated along with irinotecan at 50 & 20 µM but SN38 only at 50 µM. Our result indicates the role of TLR4 in DDI between taxol and Irinotecan and proposes the need for dose adjustment in patients with TLR4 polymorphism.