Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters.
ATP-binding cassette (ABC)-transporters, such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs) and breast cancer resistance protein (BCRP/ABCG2) transport numerous drugs thus regulating their absorption, distribution and excretion. Angiotensin receptor type 1 blockers (ARBs), used to treat hypertension and heart failure, are commonly administered in combination therapy. However, their interaction potential is not well studied and their effect on ABC-transporters remains elusive. The study therefore aimed to elucidate the effect of various ARBs (telmisartan, candesartan, candesartan-cilexetil, irbesartan, losartan, olmesartan, olmesartan-medoxomil, eprosartan) on ABC-transporter activity in vitro. P-gp inhibition was assessed by calcein assay, BCRP inhibition by pheophorbide A efflux assay, and MRP2 inhibition by a MRP2 PREDIVEZ Kit. Induction of P-gp, BCRP and MRP2 was assessed by real time reverse transcriptase polymerase chain reaction and for P-gp also in a functional assay. Telmisartan was identified as one of the most potent inhibitors of P-gp currently known (IC(50)=0.38+/-0.2 microM for murine P-gp) and it also inhibited human BCRP (IC(50)=16.9+/-8.1 microM) and human MRP2 (IC(50)=25.4+/-0.6 microM). Moreover, the prodrug candesartan-cilexetil, but not candesartan itself, significantly inhibited P-gp and BCRP activity. None of the compounds tested induced mRNA transcription of P-gp or BCRP but eprosartan and olmesartan induced MRP2 mRNA expression. In conclusion, telmisartan substantially differed from other ARBs with respect to its potential to inhibit ABC-transporters relevant for drug pharmacokinetics and tissue defense. These findings may explain the known interaction of telmisartan with digoxin and suggest that it may modulate the bioavailability of drugs whose absorption is restricted by P-gp and possibly also by BCRP or MRP2.
Weiss
J
J
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany. johanna.weiss@med.uni-heidelberg.de
Sauer
A
A
Divac
N
N
Herzog
M
M
Schwedhelm
E
E
Böger
R H
RH
Haefeli
W E
WE
Benndorf
R A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000179:Acrylates / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D001692:Biological Transport; D001713:Biphenyl Compounds / Q000378:metabolism; D004077:Digoxin / Q000378:metabolism; D005452:Fluoresceins; D006801:Humans; D006973:Hypertension; D007093:Imidazoles / Q000378:metabolism; D000077405:Irbesartan; D019808:Losartan / Q000302:isolation & purification / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D000089762:Multidrug Resistance-Associated Protein 2; D000068557:Olmesartan Medoxomil; D013777:Tetrazoles / Q000378:metabolism; D013876:Thiophenes / Q000378:metabolism
C000715087:ABCC2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005452:Fluoresceins; D007093:Imidazoles; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D013777:Tetrazoles; D013876:Thiophenes; C068373:eprosartan; D000068557:Olmesartan Medoxomil; D004077:Digoxin; C437965:olmesartan; D000077405:Irbesartan; D019808:Losartan; C077793:candesartan cilexetil; C007740:fluorexon