Transepithelial vinblastine secretion mediated by P-glycoprotein is inhibited by forskolin derivatives.
[3H]Vinblastine transport across MDCK (renal epithelial) cell layers has been characterised. The basal-to-apical [3H]vinblastine flux (JA-B) (at 10 nM) exceeded apical-to-basal flux by 19.6 fold. Net vinblastine secretion (JB-A - JA-B) was inhibited by verapamil (0.1 mM) primarily by a reduction in JB-A, consistent with net vinblastine secretion resulting from an inhibition of P-glycoprotein. 1,9-Dideoxy-forskolin and forskolin (0.1 mM) both resulted in significant inhibition of JB-A and net vinblastine secretion of 64.3 +/- 3.1% and 29.1 +/- 4.8% respectively. 7 beta-deactyl-7 beta-(gamma-N-methylpiperazino)-butyryl-forskolin was ineffective. Half-maximal inhibition of vinblastine secretion by 1,9-dideoxy-forskolin was observed at 65 microM. 1,9-dideoxy-forskolin is unable to stimulate adenylate cyclase, suggesting that this forskolin derivative is a potentially important lead antagonist of P-glycoprotein for circumvention of pleiotropic drug resistance.
Gastrointestinal Drug Delivery Research Centre, University of Newcastle upon Tyne, Medical School, UK.
J
J
Hunter
B H
BH
Hirst
N L
NL
Simmons
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004285:Dogs; D004848:Epithelium / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D005576:Colforsin; D014747:Vinblastine; D014700:Verapamil; D000262:Adenylyl Cyclases; C047983:1,9-dideoxyforskolin