Losartan is a potent, orally active, angiotensin II receptor antagonist and is used as an antihypertensive agent.1) Losartan binds selectively and specifically to the AT 1 subtype of angiotensin receptor. In contrast to angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists directly abolish the actions of angiotensin II in the body.Losartan is metabolized to EXP3174, 2-n-butyl-4-chloro-1-[(2Ј-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole-5-carboxylic acid, which contributes to the overall in vivo activity of losartan in rats 2) and humans.3) EXP3174 has a longer half-life than losartan. The conversion of losartan to EXP3174 is catalyzed by two cytochrome P450 subfamilies: CYP2C9 and CYP3A4. 4) In normal volunteers, renal clearance accounts for about 12 and 55% of the systemic clearance of losartan and EXP3174, respectively.
5)Progressive renal insufficiency is commonly accompanied by hypertension, which frequently results in the use of antihypertensive agents to reduce blood pressure or, secondarily, to provide renoprotection 6) ; accordingly, it is necessary to investigate the effect of renal failure on the pharmacokinetics of antihypertensive drugs to establish when dosage adjustment is necessary. Very limited information is available on the pharmacokinetics of losartan in humans with renal dysfunction. Sica et al. reported that the steady-state areas under the curve (AUC) of losartan and EXP3174 were not significantly changed with renal impairment. 7) On the other hand, Saruta et al. reported that the maximum serum concentration (C max ) and AUC 0-24 in patients with renal impairment were higher than those in patient with normal renal function.
8)Renal failure is commonly thought to have its sole effect on the renal elimination of drugs.9) However, in fact, renal failure has a variety of influences on drug kinetics: it reduces nonrenal drug elimination (which includes renal as well as hepatic drug metabolism), and influences protein binding and alters the volume of distribution of some drugs.10-12) Renal failure reduces the bioavailability of some drugs and increases that of others. Even for drugs which are not renally eliminated, renal failure can lead to the accumulation of toxic metabolites.9)The purpose of this investigation was to determine the effects of experimental renal failure on the pharmacokinetics of losartan in rats. Animals Male Wistar rats (8 weeks) weighting 250-302 g, were purchased from SLC Japan (Hamamatsu). Before the experiments, the rats were housed in a temperature-and humidity-controlled room with free access to water and standard rat chow. The animal experiments were performed in accordance with The Guidelines for Animal Experiments of Tokyo Medical and Dental University.
MATERIALS AND METHODS
MaterialsInduction of Acute Renal Failure To produce experimental acute renal failure (ARF), rats received a subcutaneous injection of uranyl nitrate, 10 mg/kg as a 1% solution in normal saline, about 72 h before the experiment. 13) Control animals received an injecti...
Our results suggest that CYP3A416B is associated with both reduced 3'-p-hydroxylation of paclitaxel and probably increased levels of 6alpha-hydroxypaclitaxel.
CYP2C8*IG group haplotypes were associated with increased area under concentration-time curve of C3'-p-hydroxy-paclitaxel and area under concentration-time curve ratio of C3'-p-hydroxy-paclitaxel/paclitaxel. Thus, *IG group haplotypes might be associated with reduced CYP2C8 activity, possibly through its reduced protein levels.
The CRISPR-Cas9 technology has been a powerful means to manipulate the genome in a wide range of organisms. A series of GFP knocked-in (GFP KI ) Drosophila strains have been generated through CRISPR-Cas9-induced double strand breaks coupled with homology-directed repairs in the presence of donor plasmids. They visualized specific cell types or intracellular structures in both fixed and live specimen. We provide a rapid and efficient strategy to identify KI lines. This method requires neither co-integration of a selection marker nor prior establishment of sgRNA-expressing transgenic lines. The injection of the mixture of a sgRNA/Cas9 expression plasmid and a donor plasmid into cleavage stage embryos efficiently generated multiple independent KI lines. A PCR-based selection allows to identify KI fly lines at the F1 generation (approximately 4 weeks after injection). These GFP KI strains have been deposited in the Kyoto Drosophila stock center, and made freely available to researchers at non-profit organizations. Thus, they will be useful resources for Drosophila research.
Liver stiffness measured by noninvasive VTQ methods can be used to assess liver congestion and therapeutic effects in patients with HF. (Circ J 2016; 80: 1187-1195).
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