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

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.
Authors	J J Starling, R L Shepard, J Cao, K L Law, B H Norman, J S Kroin, W J Ehlhardt, T M Baughman, M A Winter, M G Bell, C Shih, J Gruber, W F Elmquist, A H Dantzig
Journal	Advances in enzyme regulation (Adv Enzyme Regul) Vol. 37 Pg. 335-47 ( 1997) ISSN: 0065-2571 [Print] England
PMID	9381979 (Publication Type: Journal Article)
Chemical References	ATP Binding Cassette Transporter, Subfamily B, Member 1 Acridines Antineoplastic Agents Dibenzocycloheptenes Isoquinolines Quinolines Tetrahydroisoquinolines zosuquidar trihydrochloride Verapamil Quinidine Elacridar
Topics	ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism) Acridines (pharmacology) Animals Antineoplastic Agents (pharmacokinetics, pharmacology) Dibenzocycloheptenes (pharmacokinetics, pharmacology, therapeutic use) Drug Resistance, Multiple Drug Resistance, Neoplasm Humans Isoquinolines (pharmacology) Mice Mice, Inbred Strains Neoplasms, Experimental (drug therapy) Quinidine (metabolism) Quinolines (pharmacokinetics, pharmacology, therapeutic use) Structure-Activity Relationship Tetrahydroisoquinolines Tumor Cells, Cultured Verapamil (metabolism, pharmacology)

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