digoxin and olmesartan

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.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Benzimidazoles; Biological Transport; Biphenyl Compounds; Digoxin; Fluoresceins; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Membrane Transport Proteins; Mice; Multidrug Resistance-Associated Protein 2; Olmesartan Medoxomil; Tetrazoles; Thiophenes

The objective of this study was to determine an appropriate culture period to assess whether a compound of interest is transported by efflux transporters such as human multidrug resistance 1 (hMDR1), human multidrug resistance-associated protein 2 (hMRP2), and human breast cancer resistance protein (hBCRP) in Caco-2 cells. Caco-2 cells were cultured on a Transwell for 1 to 6 weeks. The expression of these transporters in the mRNA and protein levels was examined using a real-time polymerase chain reaction and Western blotting, respectively. Transcellular transport activities using digoxin, ochratoxin A, olmesartan, and estrone-3-sulfate were also examined. Except for digoxin, the permeability coefficient (P(app)) ratio of the three compounds at 2 weeks was the highest in the periods tested. The P(app) ratio of digoxin at 2 weeks was higher than that at 3 weeks. The temporal expression profile of each transporter in the mRNA level was similar to that in the protein level, and the functions of hMRP2 and hBCRP were roughly correlated with the expression in the mRNA and protein levels, but that of hMDR1 was not. These data suggest that among all the culture periods evaluated a 2-week culture is the best culture period for transport studies to identify whether a compound is a substrate for hMDR1, hMRP2, and hBCRP.

Topics: Angiotensin II Type 1 Receptor Blockers; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Blotting, Western; Caco-2 Cells; Calcium Channel Blockers; Digoxin; Electric Conductivity; Estrone; Humans; Imidazoles; Leukotriene Antagonists; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ochratoxins; Propionates; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazoles; Tight Junctions; Time Factors; Verapamil

Orally administered olmesartan medoxomil was rapidly absorbed from the gastrointestinal tract and converted during absorption to olmesartan, the pharmacologically active metabolite that was subsequently excreted without further metabolism. The medoxomil moiety was released as diacetyl that was rapidly cleared by further metabolism and excretion. Peak plasma concentrations of olmesartan occurred 1-3 h after administration, after which concentrations decreased quickly. The elimination half-life was 10-15 h. Olmesartan medoxomil was not measurable in plasma and excreta. The volume of distribution was low, consistent with limited extravascular tissue distribution. Bioavailability (Cmax and area under the curve) increased approximately in proportion with dose, after single and multiple daily oral doses, over the therapeutic dose range (up to 40-80 mg daily), above which systemic availability of olmesartan increased less than proportionally with increase in dose. Steady-state plasma concentrations of olmesartan were reached within the first few daily oral doses. On average, approximately 40% of systemically available olmesartan was excreted by the kidneys, the remainder being excreted in faeces, following secretion in bile. Renal clearance (0.5-0.7 l/h) was independent of dose, accounting for approximately 9-12% of an oral dose. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets was 28.6%. Olmesartan exhibited little or no binding to blood cells. No clinically significant steady-state pharmacokinetic interactions were observed following co-administration of olmesartan medoxomil with digoxin, warfarin and aluminium magnesium hydroxide (antacid), supporting the low potential for clinically significant pharmacokinetic interactions to occur between olmesartan medoxomil and co-administered drugs.

Topics: Administration, Oral; Adult; Aluminum Hydroxide; Biological Availability; Blood; Digoxin; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Humans; Hydrolysis; Imidazoles; Injections, Intravenous; Magnesium Hydroxide; Male; Olmesartan Medoxomil; Tetrazoles; Warfarin