title: CJX1, an amlodipine derivative, interacts with ATPase of human P-glycoprotein.
abstract: Our aim has been to elucidate the possible mechanism of CJX1, an amlodipine derivative, in the modulation of P-gp function by determining its effect on P-gp ATPase activity. Basal P-gp ATPase activity was increased by CJX1 with half-maximal activity concentration (Km) of 8.6+/-1.4 microM. Kinetic analysis indicated a non-competitive inhibition of Verapamil (Ver)-stimulated P-gp ATPase activity by CJX1 and competitive inhibition of CJX1-stimulated P-gp ATPase activity by tetrandrine (Tet). The effect of CsA on CJX1-stimulated and Ver-stimulated P-gp ATPase activity was non-competitive and competitive inhibition, respectively. These findings implying that CJX1 and Tet can bind P-gp either on overlapping sites or distinct but interacting sites, while CJX1 and Ver as well as CsA can bind P-gp on separated sites in K562/DOX cells. Furthermore, the combined effect of CJX1 and Ver has been evaluated isobolographically in numerous fixed-ratio combinations of 1:1, 1:2, 1:4, 1:8, 1:10 in K562/DOX cells. The results show that mixtures of both drugs at these fixed-ratios exerted synergistic interactions, indicating that when the two reverses that bind P-gp on separated sites are combined, each can contribute to the overall interaction with P-gp, leading to the greater effect than that by either agent alone.
authors: Institute of Pharmacy, Henan University, Kaifeng 475001, PR China.
authors: Bian-Sheng
authors: BS
authors: Ji
authors: Ling
authors: L
authors: He
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism*; D017311:Amlodipine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044182:Benzylisoquinolines; C504653:CJX1, amlodipine derivative; D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D017311:Amlodipine; C009438:tetrandrine; D016572:Cyclosporine; D014700:Verapamil; D000251:Adenosine Triphosphatases