eprosartan and candesartan-cilexetil

Angiotensin II (Ang II) has diverse physiological actions leading, for example, to increases in extracellular volume, peripheral vascular resistance and blood pressure, and has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated as AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone and the release of arginine vasopressin (AVP). In each condition the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum AVP levels or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor reportedly exerts antiproliferative effects and promotes neurite outgrowth, an effect accompanied by significant changes in the gene expression pattern of growth- and differentiation-related genes.

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Tetrazoles; Thiophenes

The angiotensin II (AII) type 1 receptor antagonists represent a new pharmacologic class of drugs that are specifically designed to displace AII from its type 1 receptor subtype. These drugs antagonize AII-induced biologic actions, including smooth-muscle contraction, sympathetic pressor mechanisms, and aldosterone release. Initial clinical trials suggest that these drugs are effective in the treatment of essential hypertension and hypertensive patients with intrinsic renal disease. Thus, they are the newest addition to the therapeutic armamentarium for the treatment of hypertensive diseases. We review the developmental history and pharmacology of the AII type 1 receptor antagonists. We specifically discuss the following factors: mechanism(s) of action; members under clinical investigation; effects on renal function, salt and water excretion, and plasma renin activity, plasma AII type 1, and plasma aldosterone concentrations; and efficacy and safety. Given the demonstrable benefits of AII type 1 receptor blockade, these drugs should achieve broad utility in the treatment of hypertensive diseases.

Topics: Acrylates; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Humans; Imidazoles; Irbesartan; Losartan; Pyridines; Quinolines; Telmisartan; Tetrazoles; Thiophenes; Valine; Valsartan

Topics: Acrylates; Angiotensin Receptor Antagonists; Benzimidazoles; Biphenyl Compounds; Chlorthalidone; Chromatography, High Pressure Liquid; Hydrochlorothiazide; Imidazoles; Irbesartan; Losartan; Molecular Structure; Software; Tablets; Tetrazoles; Thiophenes; Valsartan

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