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

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.

Interaction Potential of Etravirine with Drug Transporters Assessed In Vitro

“…In the BCRP/ABCG2 inhibition assay, etravirine increased pheophorbide A fluorescence in MDCKII-BCRP cells but not in the parental cell line MDCKII, indicating BCRP/ABCG2 inhibition (IC 50 of 1.0 Ϯ 0.4 mol/liter). The IC 50 was similar to the IC 50 for fumitremorgin C (FTC) (0.7 Ϯ 0.3 mol/liter [25]), one of the most potent BCRP/ABCG2 inhibitors known. Effective etravirine concentrations match maximum plasma concentrations of etravirine, which have been reported to be in the range of 1.34 Ϯ 0.36 g/ml (equal to 3.1 mol/liter, yielding 3.1 nmol/liter unbound drug) on day 8 after administration of the approved dosage of 200 mg twice daily (18).…”

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

“…[17,18] Rosuvastatin is a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, OATP2B1, and NTCP) and efflux transporters such as BCRP, and there are many clinically meaningful DDI data. [15,19,20] Telmisartan is an inhibitor of MRP, BCRP in in vitro, [21] but, as yet, there is no reported case of clinical transporter-mediated DDI of telmisartan as a perpetrator. In our final model, telmisartan affects the absorption process of rosuvastatin rather than its metabolic elimination.…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Moreover, some ARBs are inhibitors of P-gp that may lead to drug-drug interactions (see Section VI.G). Thus, telmisartan was shown to block digoxin transport in vitro with an IC 50 of 2.19 mM (Kamiyama et al, 2010), whereas candesartan cilexetil and irbesartan were less potent (IC 50 14.7 and 34 mM, respectively), and losartan, eprosartan, and candesartan did not inhibit P-gp (Kamiyama et al, 2010;Weiss et al, 2010). Given the intestinal concentration of telmisartan, telmisartan is potent enough to be expected to affect oral bioavailability of P-gp substrates in the intestine.…”