Disease relevance of Exp3174

• Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life [1].
• CONCLUSIONS: The pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure [2].

Psychiatry related information on Exp3174

• Following 8 h water deprivation in Brattleboro rats, neither EXP 3174 nor PD 123319 inhibited drinking when water was returned [3].

High impact information on Exp3174

• The facilitatory effect of Ang II was blocked by either the peptide Ang II receptor antagonist saralasin (1.0 mumol/L) or EXP 3174 (0.1 mumol/L), the in vitro active form of the nonpeptide Ang II receptor antagonist losartan [4].
• Background and aim Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo [5].
• The urinary losartan/E-3174 ratio of the single CYP2C9*1/*6 subject was higher than the 95% confidence interval of the mean of the CYP2C9*1/*1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9*8/*11 carrier was inside the 95% confidence interval of the means of the CYP2C9*1/*1 and CYP2C9*1/*11 groups (0.0-18) [5].
• RESULTS: The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9*1/*1, 14.6 for CYP2C9*1/*5, 4.2 for CYP2C9*1/*6, 188 for CYP2C9*5/*6, 11.6 for CYP2C9*5/*8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9*1/*8, 2.2 for CYP2C9*8/*11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9*1/*11 [5].
• Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype [6].

Biological context of Exp3174

• Effect of EXP 3174 on blood pressure of normoreninemic renal hypertensive rats [7].
• RESULTS: The maximum plasma concentration of E-3174 was significantly (P <.05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype [6].
• Our aim was to evaluate the pharmacokinetics of losartan and E-3174 in relation to the CYP2C9 genotype [6].
• CONCLUSION: Chronic, but not acute, administration of EXP 3174 normalized baroreflex function in SHR [8].
• HR 720 blocked the increase in protein synthesis with potency similar to EXP 3174; the respective IC50 values were 1.04 x 10(-9) M and 1.36 x 10(-9) M [9].

Anatomical context of Exp3174

• DuP 753 or EXP 3174 (40 micrograms in 100 nl artificial cerebrospinal fluid vehicle) or vehicle alone was microinjected into the anterior hypothalamic area of conscious salt-sensitive spontaneously hypertensive and Wistar-Kyoto rats that had been fed 1% or 8% salt diets for 3 weeks [10].
• EXP 3174 was also given subcutaneously for 15 days (5 mg/kg per day) in SHR, and baroreceptor reflex activity was assessed approximately 24 h later [8].
• Captopril (n = 12), ramiprilat (n = 10) or EXP 3174 (n = 9) was infused into the renal artery in graded doses to examine whether the threshold dose that increased RBF was lower than that which increased sodium excretion rate (Na+ excretion rate) [11].
• Losartan and EXP 3174 were not toxic for human mesangial cells at the concentrations studied as judged by the absence of release of lactate dehydrogenase and the normal uptake of neutral red [12].
• Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers [13].

Associations of Exp3174 with other chemical compounds

• Both DuP 753 and EXP 3174 caused significant decreases in mean arterial pressure in spontaneously hypertensive but not in Wistar-Kyoto rats fed either diet [10].
• The concentration-response curves of Ang I and Ang II were shifted to the right by EXP 3174 (0.01 mumol), the in vitro active form of the Ang II type 1 receptor antagonist losartan, with affinity estimates of 8.72 and 9.30, respectively [14].
• To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects [1].
• A capillary zone electrophoretic (CZE) method was optimized for the separation of five angiotensin II receptor antagonists (Losartan, Irbesartan, Valsartan, Telmisartan and Eprosartan) and two of their metabolites (EXP 3174 and Candesartan M1) by means of experimental design methodologies [15].
• UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 28 +/- 6 nM, 3504 +/- 892 nM and 21 +/- 3 nM, respectively [16].

Gene context of Exp3174

• OBJECTIVE: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro [17].
• Our study demonstrated that acute blockade of the AT1 receptor with E-3174 reduced elevated pre- and after-load and consequently increased stroke volume in a canine HF model [18].
• Reflex elevation of plasma renin activity induced by 1 mg/kg of E-3174 was similar to that caused by 1 mg/kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system [18].
• The present study suggests that CYP2D6 and CYP2C19 are not involved to any major extent in the in vivo conversion of losartan to E-3174 [19].
• These effects appeared to be essentially mediated by AT1 receptor stimulation as indicated by the equal inhibitory effects of HR 720 and EXP 3174 [9].

Analytical, diagnostic and therapeutic context of Exp3174

• Losartan and E-3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake [6].
• In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112 +/- 6 to 96 +/- 6mm Hg, P < .05) [7].
• After oral administration approximately 14% of a losartan dose is converted to the pharmacologically active E 3174 metabolite [20].
• In addition, this compound produced a marked and long-lasting decrease in blood pressure in high renin animal models and proved to be superior to the corresponding tetrazole 45 as well as to DuP 753 or its active metabolite EXP 3174 [21].
• Plasma concentrations of losartan and E-3174 were assayed by high-performance liquid chromatography with mass spectrometry detection [22].

References