Pharmacological characterization of LY335979: a potent cyclopropyldibenzosuberane modulator of P-glycoprotein

Adv Enzyme Regul. 1997;37:335-47. doi: 10.1016/s0065-2571(96)00021-0.

Abstract

The above data indicate that LY335979 displays the following characteristics of an 'ideal modulator' of Pgp-mediated multidrug resistance: high affinity binding to Pgp, high potency for in vitro reversal of drug resistance, high therapeutic index (activity was demonstrated at doses ranging from 1-30 mg/kg) observed in in vivo antitumor efficacy experiments, and a lack of pharmacokinetic interactions that alter the plasma concentration of coadministered oncolytic agents. These desirable features strongly suggest that LY335979 is an exciting new clinical agent to test the hypothesis that inhibition of P-glycoprotein activity will result in reversal of multidrug resistance in human tumors.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Acridines / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Dibenzocycloheptenes / pharmacokinetics
  • Dibenzocycloheptenes / pharmacology*
  • Dibenzocycloheptenes / therapeutic use
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Humans
  • Isoquinolines / pharmacology
  • Mice
  • Mice, Inbred Strains
  • Neoplasms, Experimental / drug therapy
  • Quinidine / metabolism
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology*
  • Quinolines / therapeutic use
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines*
  • Tumor Cells, Cultured
  • Verapamil / metabolism
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acridines
  • Antineoplastic Agents
  • Dibenzocycloheptenes
  • Isoquinolines
  • Quinolines
  • Tetrahydroisoquinolines
  • zosuquidar trihydrochloride
  • Verapamil
  • Quinidine
  • Elacridar