title: Role of Toll-like receptor 4 in drug-drug interaction between paclitaxel and irinotecan in vitro.
abstract: The bacterial receptor, Toll-like receptor (TLR) 4 mediates inflammatory responses and has been linked to a broad array of diseases. TLR4 agonists are being explored as potential treatments for cancer and other diseases. We have previously shown that activation of TLR4 by lipopolysaccharide (LPS) leads to down-regulation of drug metabolizing enzymes/transporters (DMETs), and altered pharmacokinetics/pharmacodynamics (PK/PD) of drugs. These changes can increase the risk of drug-drug interactions (DDIs) in patients on multiple medications. Clinically, DDI was observed for combination chemotherapy of paclitaxel (TLR4 ligand) and irinotecan. To determine the role of TLR4 in DDI between paclitaxel and irinotecan in vitro, primary hepatocytes from TLR4-wild-type (WT) and mutant mice were pre-treated with paclitaxel, followed by irinotecan. Gene expression of DMETs was determined. Paclitaxel treatment increased the levels of irinotecan metabolites, SN-38 and SN-38 glucuronide (SN-38G) in TLR4-dependent manner. Paclitaxel-mediated induction of genes involved in irinotecan metabolism such as Cyp3a11 and Ugt1a1 was TLR4-dependent, while induction of the transporter Mrp2 was TLR4-independent. These novel findings demonstrate that paclitaxel can affect irinotecan metabolism by a TLR4-dependent mechanism. This provides a new perspective towards evaluation of marketed drugs according to their potential to exert DDIs in TLR4-dependent manner.
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
authors.forename: Pankajini
authors.initials: P
authors.lastname: Mallick
authors.affiliation: Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Bhagavtula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. Electronic address: rghose@uh.edu.
authors.forename: Romi
authors.initials: R
authors.lastname: Ghose
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D043182:Carboxylesterase / Q000378:metabolism; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D000077146:Irinotecan; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099148:UGT1A1 Enzyme
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D043182:Carboxylesterase; D051544:Cytochrome P-450 CYP3A; D016207:Cytokines; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008565:Membrane Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D051197:Toll-Like Receptor 4; D000097202:ATP-Binding Cassette Sub-Family B Member 4; D000099148:UGT1A1 Enzyme; C496508:Cyp3a11 protein, mouse
keywords: Drug metabolizing enzymes; Drug-drug interactions; Irinotecan; Paclitaxel; Toll-like receptor 4