Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters.

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Weiss J, Sauer A, Divac N, Herzog M, Schwedhelm E, Boger RH, Haefeli WE, Benndorf RA

Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters.

Biopharm Drug Dispos. 2010 Mar;31(2-3):150-61. doi: 10.1002/bdd.699.

PubMed ID

20222053 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Eprosartan	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Inducer	Details
Olmesartan	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Substrate Inducer	Details
Telmisartan	ATP-binding cassette sub-family G member 2	Protein	Humans	Unknown	Inhibitor	Details
Telmisartan	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Inhibitor	Details
Telmisartan	P-glycoprotein 1	Protein	Humans	Unknown	Inhibitor	Details