"Effect of the drug transporters ABCB1, ABCC2, and ABCG2 on the disposition and brain accumulation of the taxane analog BMS-275,183"

Invest New Drugs. 2014 Dec;32(6):1083-95. doi: 10.1007/s10637-014-0143-0. Epub 2014 Jul 31.

Abstract

BMS-275,183 is a novel oral C-4 methyl carbonate analogue of paclitaxel. Recently, a drug-drug interaction between BMS-275,183 and benzimidazole proton pump inhibitors (PPIs) was suggested in clinical trials resulting in elevated drug exposure and toxicity. We explored whether the interaction takes place at the level of P-glycoprotein (Pgp, MDR1, ABCB1), Breast Cancer Resistance Protein (BCRP, ABCG2) and MRP2 (ABCC2) using in vitro and in vivo models. In vitro cell survival, drug accumulation, efflux and transport studies with BMS-275,183 were performed employing MDCKII (wild-type, MDR1, BCRP, MRP2) and LLCPK (wild-type and MDR1) cells. In vivo the pharmacokinetics and tissue distribution of BMS-275,183 after p.o. and i.v. administration were explored in Mdr1a/1b(-/-) and wild-type mice, in presence or absence of the PPI pantoprazole. Results In vitro, BMS-275,183 was found to be a good substrate for MDR1, a moderate substrate for MRP2 and not a substrate for BCRP. In vivo, oral bioavailability, plasma AUC0-6h and brain concentrations were significantly 1.5-, 4-, and 2-fold increased, respectively, in Mdr1a/1b(-/-) compared with wild-type mice (p < 0.001). However, oral co-administration of pantoprazole (40 mg/kg) did not alter the pharmacokinetics of BMS-275,183 in wild-type mice. Conclusions BMS-275,183 is efficiently transported by Pgp and to a lesser extent by MRP2 in vitro. Genetic deletion of Pgp significantly altered the pharmacokinetics and brain distribution of p.o. and i.v. administered BMS-275,183 in Mdr1a/1b-/- compared to wild-type mice. Oral co-administration of BMS-275,183 with pantoprazole did not affect the pharmacokinetics of BMS-275,183 in wild-type mice, suggesting no interaction with PPI at the dose employed.

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles / pharmacology
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Brain / metabolism
  • Bridged-Ring Compounds / blood
  • Bridged-Ring Compounds / pharmacokinetics*
  • Bridged-Ring Compounds / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Dibenzocycloheptenes / pharmacology
  • Dogs
  • Drug Interactions
  • Female
  • Humans
  • Kidney / metabolism
  • Lung / metabolism
  • Mice, Knockout
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Myocardium / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Paclitaxel / pharmacology
  • Pantoprazole
  • Quinolines / pharmacology
  • Spleen / metabolism
  • Swine
  • Tissue Distribution

Substances

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcg2 protein, mouse
  • Antineoplastic Agents
  • BMS-275183
  • Bridged-Ring Compounds
  • Dibenzocycloheptenes
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Quinolines
  • multidrug resistance-associated protein 2
  • zosuquidar trihydrochloride
  • Pantoprazole
  • Paclitaxel