Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy.The ARBs specifically block the interaction of angiotensin II at the AT 1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development.The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect.Keywords: angiotensin receptor blockers; candesartan; eprosartan; irbesartan; losartan; telmisartan; valsartan; pharmacokinetics After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels ‫؍‬ 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavaila...

Probenecid, its metabolites (including 14C labeled), and several analogs were synthesized. The uv spectral properties, p.Ka's, and partition coefficients were determined. The binding of probenecid and metabolites to human plasma, human albumin, and dog plasma was measured. Pmr parameters of probenecid, its metabolites, and 9 other analogs were obtained. There was no correlation between the nature of the alkyl side-chain substituents or the partition coefficient and the chemical shifts of the aromatic ring protons. In rats all the metabolites with a single exception were terminal metabolites; similar results were obtained in vitro. Propionic acid was identified as one of the metabolic products of probenecid. The effects on urate clearance of probenecid, the various metabolites, and the piperidyl analog were determined in Dalmatian and mongrel dogs. In Dalmatians the clearance decreased while in mongrels it increased. Our studies suggest that the metabolites of probenecid may very well play a significant role in the overall uricosuric effect of the parent drug.The structures of essentially all the metabolites of probenecid in rat bile1 and human urine2'4 have been elucidated.The major routes of biotransformation are oxidation of the side chain (Figure 1, Table I) and glucuronide conjugation. In man, formation of the acyl glucuronide accounts for the disposition of about 0.2 of the drug.2'3 Incubation of probenecid-^C with reinforced rat liver preparations leads to the same metabolites as found in vivo.5The purpose of the present study was (1) to synthesize the metabolites (labeled and unlabeled) of probenecid, (2) to learn whether they could contribute to the overall pharmacologic activity of the parent drug, and (3) to extend previous investigations of structure-activity relationships in this series.6 The latter studies included detailed analyses of high-resolution proton magnetic resonance (pmr) spectra, pAa determinations, and measurement of drug-protein binding. Experimental SectionA. Synthesis.Our general procedure for synthesis of probenecid analogs (adapted from Miller7) was: to an ice-cold soln of the appropriate secondary amine (0.12 mole) in 25 ml of anhyd MeOH 8.8 g (0.040 mole) of p-(chlorosulfonyl)benzoic acid (1)1 was added and the mixt stirred at room temp overnight. The MeOH was removed in vacuo and the oily residue taken up in 25 ml of H20. The pH was adjusted to 1 with coned HC1 and the resulting ppt collected by filtration, then dissolved in a slight excess of 0.1 N NaOH (pH >10). After one extn with Et20 and repptn with HC1, the compd was crystd from EtOH-H20, with prior charcoal treatment, and dried at 110°in vacuo. Purity of the analogs was detd by capillary mp in a Thomas-Hoover Uni-Melt, by known Rf values on tic,2 and by elemental analysis. The 14C compds# were synthesized by a modification of the procedure of Motoichi, et al.8 Ring 14C-labeled probenecid and some nonlabeled analogs were a gift from Dr.

The relationship between PPC and its effect on minoxidil-induced increases in PHA and heart rate was examined in 9 patients with essential hypertension. Concomitant with the minoxidil-induced depression of mean arterial pressure (30.7 ± 3.5 mm Hg, mean ± SEM), heart rate increased from 79.1 ± 3.0 to 100.4 ± 4.6 BPM, and PHA increased from 1.12 ± 0.28 to 8.58 ± 2.83 nglmllhr. Addition of propranolol to minoxidil caused a decrease in heart rate in proportion to log PPC:~ heart rate = 1.1 -12.8 log PPC (r, 0.59, p < 0.005) The relationship between PPC and the reduction in PHA was more complex. While a maio! reduction in PHA was observed at PPC in the range 20 to 60 nglmllhr, there was no consistent effect on PHA at higher PPC. Therefore, maximum antagonism of adrenergicaUy mediated increases in PHA is produced by much lower concentrations of propranolol than maximum suppression of adrenergically mediated increases in heart rate.