The pharmacokinetics of a selective AT1‐subtype, nonpeptide, orally active, angiotensin II receptor antagonist, losartan, were characterized in 11 patients with heart failure (New York Heart Association class II, n = 6; class III, n = 4; class IV, n = 1) after oral and intravenous administration. In these patients, average plasma clearance of losartan was 566 mL/min, volume of distribution at steady‐state was 34 L, and terminal plasma half‐life was 1.5 hours. Average bioavailability was 36%. No clinically significant accumulation of losartan or its active metabolite, EXP3174, occurred after multiple‐dose oral administration for 7 to 8 days. Terminal plasma half‐life of EXP3174 after oral administration of losartan was 7.6 hours. The pharmacokinetics of losartan in patients in this study appear to be similar to those in healthy subjects studied previously.

There is mounting experimental evidence that blocking angiotensin receptor type 1 activity can prevent the occurrence of hypertension in spontaneously hypertensive rats. Studies have proved this strategy via evasive means, such as intracerebrovascular injections, making clinical translation difficult. This study aimed to develop penetratin and transferrin functionalized liposomes as a delivery tool to safely deliver losartan potassium (an angiotensin receptor blocker) to the brain. Penetratin and transferrin functionalized losartan-loaded liposomes were prepared via the post-insertion technique. Losartan-loaded liposomes were cationic, approximately 150 nm in size, entrapping 66.8 ± 1.5% of losartan. All formulations were well tolerated and internalized by primary and cultured cells in 4 h.Further, the ability to deliver losartan potassium across the blood–brain barrier was evaluated in vivo in Wistar Kyoto rats either in solution or when encapsulated within liposomal nanoparticles. Upon intravenous administration, we did not find a detectable amount of losartan in the brain tissue of rats that received free losartan solution. Contrarily, liposome formulations could deliver losartan to the brain, with a brain AUC and mean resident time of 163.304 ± 13.09 and 8.623 h ± 0.66, respectively. In addition, no toxicity was observed in the animals that received the losartan-loaded liposomes.

We investigated the tolerability and angiotensin II antagonist activity of oral DuP 532 in healthy male subjects. DuP 532 (1 to 200 mg) was well tolerated, with no effect on blood pressure or heart rate. Compared with losartan (100 mg), DuP 532 (200 mg) was a weak antagonist of presser responses to intravenous angiotensin II. Maximum inhibition of diastolic presser response was 86% (95% confidence interval [CI], 84%, 88%) approximately 4.6 hours after losartan and 48% (95% CI, 38%, 56%) 8.7 hours after Dull 532. Twenty-four hours after dosing, inhibition by losartan and DuP 532 was similar (40% to 45%). DUP 532 is extensively bound in human plasma, with an in vitro free fraction of 0.06. Although DuP 532 and EXP3174 (losartan's active metabolite) have similar AT(1)-receptor potency, and plasma concentrations of DuP 532 were much greater than losartan/EXP3l74, the level of antagonism was much less for DuP 532. These results indicate that multiple factors determine the in vivo potency of angiotensin II antagonists, including affinity for and distribution to the receptor as modulated by plasma binding.

Clinical Pharmacology & Therapeutics (1996) 59, 169–169; doi: 10.1038/sj.clpt.1996.177

Aim: To determine the effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of losartan (MK-954) and its metabolite E3174 Patients and methods: A two-center, unblinded trial was performed in 18 patients (age range 31–63 years) with various degrees of renal function grouped according to the renal clearance of creatinine: group I, creatinine clearance >75 ml/min; group II, creatinine clearance 30–74 ml/min; group III, creatinine clearance 10–29 ml/min (n=6 in all groups). Losartan (100mg/day) was administered under supervised conditions for seven consecutive days. Plasma samples were taken for up to 60 h and 24-h urine collections were made following the final dose of losartan (on day 7) to determine losartan and E 3174 concentrations, with simultaneous measurements of blood pressure and the pulse rate Results: The pharmacokinetic parameters for losartan and E3174 changed inconsequentially across the range of renal insufficiency. For losartan, renal clearance decreased from 50± 19 ml/min in group I to 2.3 ±0.9 ml/min in group III (P<0.05). For E31 74, although the renal clearance decreased from 16±4.1 ml/min in group I to 1.3 ±0.8 ml/min in group III (P<0.05), the area under the plasma concentration curve did not change Conclusions: The steady-state areas under the curve of losartan and E3174 are not significantly changed with renal impairment. The renal clearance of losartan decreases with renal impairment but since only a small percentage of the dose is ordinarily eliminated by the kidney, the demonstrated reduction in clearance is clinically irrelevant. The renal clearance of E3174 also decreases with renal impairment, but the steady-state area under the curve does not increase with increasing degrees of renal insufficiency. These pharmacokinetic alterations do not warrant dose adjustment in the face of renal insufficiency

The pharmacokinetics of the angiotensin II receptor antagonist losartan potassium and its active carboxylic acid metabolite EXP3174 were characterized in 18 healthy male subjects after administration of intravenous losartan, intravenous EXP3174, and oral losartan. In these subjects, the average plasma clearance of losartan was 610 ml/min, and the volume of distribution was 34 L. Renal clearance (70 ml/min) accounted for 12% of plasma clearance. Terminal half-life was 2.1 hours. In contrast, the average plasma clearance of EXP3174 was 47 ml/min, and its volume of distribution was 10 L. Renal clearance was 26 ml/min, which accounted for 55% of plasma clearance; terminal half-life was 6.3 hours. After oral administration of losartan, peak concentrations of losartan were reached in 1 hour. Peak concentrations of EXP3174 were reached in 3 1/2 hours. The area under the plasma concentration-time curve of EXP3174 was about four times that of losartan. The oral bioavailability of losartan tablets was 33%. The low bioavailability was mainly attributable to first-pass metabolism. After intravenous or oral administration of losartan the conversion of losartan to the metabolite EXP3174 was 14%.

A sensitive and selective high-performance liquid chromatographic method for the simultaneous determination of a new angiotensin II receptor blocking agent, losartan (DuP 753, MK-954, I), and its active metabolite, EXP3174 (II), in human plasma or urine is described. The two analytes and internal standard are extracted from plasma and urine at pH 2.5 by liquid—liquid extraction and analyzed on a cyano column with ultraviolet detection at 254 nm. The mobile phase is composed of acetonitrile and phosphate buffer at pH 2.5. The limit of quantification for both compounds in plasma is 5 ng/ml. The limit in urine is 20 and 10 ng/ml for I and II, respectively. The assay described has been successfully applied to samples from pharmacokinetic studies.