Tropane alkaloids as substrates and inhibitors of human organic cation transporters of the SLC22 (OCT) and the SLC47 (MATE) families.
Tropane alkaloids and their derivatives are anticholinergic drugs with narrow therapeutic range. Here we characterize the organic cation transporters from the SLC22 (OCT1, OCT2, and OCT3) and the SLC47 families (MATE1 and MATE2-K) as potential mediators of the renal and extra-renal excretion, the two major roads of elimination of these substances. All analyzed compounds inhibited and the quaternary amine derivatives ipratropium and trospium were strongly transported by OCTs and MATEs. Overexpression of OCTs or MATEs in HEK293 cells resulted in an up to 63-fold increase in the uptake of ipratropium (Km of 0.32 μm to OCT2 and Vmax of 3.34 nmol×mg protein-1×min-1 to MATE1). The transcellular transport of ipratropium was 16-fold higher in OCT2-MATE1 and 10-fold higher in OCT1-MATE1 overexpressing compared to control MDCKII cells. Genetic polymorphisms in OCT1 and OCT2 affected ipratropium uptake and clinically relevant concentration of ondansetron and pyrithiamine inhibited ipratropium uptake via MATEs by more than 90%. This study suggests that OCT1, OCT2 and MATEs may be strongly involved in the renal and extra-renal elimination of ipratropium and other quaternary amine alkaloids. These substances have a notoriously narrow therapeutic range and the drug-drug interactions suggested here should be further critically evaluated in humans.
Jiayin
J
Chen
Jürgen
J
Brockmöller
Tina
T
Seitz
Jörg
J
König
Xijing
X
Chen
Mladen V
MV
Tzvetkov
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004285:Dogs; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D009241:Ipratropium / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D014326:Tropanes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D050482:Catecholamine Plasma Membrane Transport Proteins; D027701:Organic Cation Transport Proteins; D014326:Tropanes; D009241:Ipratropium