Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. ADMA is generated by protein methyltransferase (PRMT) and is metabolized mainly by dimethylarginine dimethylaminohydrolase (DDAH). ADMA levels are reported to increase in patients with chronic kidney disease (CKD), thereby playing a role in the pathogenesis of accelerated atherosclerosis in this population. However, the precise mechanism underlying ADMA accumulation in these patients is not fully understood. This study investigated the molecular mechanism for the elevation of ADMA levels in CKD, using a rat remnant kidney model that represents progressive CKD. After male Sprague-Dawley rats underwent baseline measurement of BP and renal function, 5/6 subtotal nephrectomy (5/6Nx) and 4/6 nephrectomy were performed. Plasma and urinary levels of ADMA and symmetric dimethylarginine, an inert isomer of ADMA, were measured by HPLC. Expression levels of PRMT genes and DDAH proteins were analyzed by semiquantitative reverse transcription-PCR and Western blotting, respectively. Plasma ADMA levels were elevated in the Nx groups in proportion to the degree of nephrectomy despite marked increases in renal clearance of ADMA. In contrast, renal clearance of symmetric dimethylarginine was decreased and its plasma levels were increased in the Nx groups. Furthermore, both liver and kidney gene expression of PRMT was increased, whereas DDAH protein expression was decreased in the 5/6Nx group. Plasma ADMA levels were correlated with systolic BP levels. Moreover, adenovirus-mediated DDAH gene transfer into the 5/6Nx rats prevented the elevation of BP levels, which was associated with the reduction of plasma and urinary ADMA levels. The results presented here suggest that decreased DDAH levels as well as increased PRMT gene expression could cause the elevation of plasma ADMA levels, thereby eliciting hypertension in CKD. Substitution of DDAH protein or enhancement of its activity may become a novel therapeutic strategy for the treatment of hypertension-related vascular injury in CKD.

Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). It was recently reported that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of chronic kidney disease (CKD). ADMA is a strong predictor of the progression of CKD as well. However, a role for the ADMA-DDAH in the pathogenesis of CKD remains to be elucidated. This study investigated the effects of DDAH-elicited ADMA lowering on renal function and pathology in a rat remnant kidney model. Four weeks after five-sixths subtotal nephrectomy (Nx), the rats were given tail-vein injections of recombinant adenovirus vector encoding DDAH-I (Adv-DDAH) or control vector expressing bacterial ␤-galactosidase The synthesis of NO can be blocked by inhibition of the NOS active site with guanidino-substituted analogues of l-arginine, such as asymmetric dimethylarginine (ADMA) (1,2). We, along with others, have demonstrated that elevated plasma ADMA is associated with cardiovascular risk factors such as hypertension (3,4), diabetes (4,5), and chronic kidney disease (CKD) (6,7), thereby being one of the useful biomarkers for atherosclerosis and future cardiovascular events (5,7-9). ADMA is mainly metabolized by an enzyme dimethylarginine dimethylaminohydrolase (DDAH) (1,2). We recently found that reduced DDAH expression could contribute to ADMA accumulation and subsequent elevation of BP in an experimental model of CKD (10). Furthermore, plasma level of ADMA is known to be a strong predictor of the progression of renal dysfunction in patients with CKD (11,12). According to the recent comprehensive review on the potential role of ADMA in renal disease progression (13), there may be two major possible mechanisms by which ADMA could contribute to the progression of CKD; one is a BP-dependent effect of ADMA described previously (4,10), and the other is a BP-independent, direct effect of ADMA on renal microvasculature. As to the latter, Kang et al. (14) demonstrated that administration of an inhibitor of NOS accelerated renal injury and impaired angiogenic response and peritubular capillary formation in the remnant kidney model, whose harmful effects were greater than expected from the increase in BP levels, thus suggesting that an important role of NO in maintaining renal microvasculature (15,16). Therefore, it is plausible that DDAH could protect against renal damage by suppressing the inhibitory effect of ADMA on NO generation. In this study, we investigated the effects of DDAH-elicited ADMA lowering on renal function and tubulointerstitial changes in a rat remnant kidney model. To address the issue of whether DDAH could protect against renal injury in a BPindependent manner, we compared the renoprotective effects of DDAH with those of hydralazine (Hyz), an antihypertensive drug with equihypotensive property.

Background: S‐mephenytoin 4’‐hydroxylase (CYP2C19) catalyses the metabolism of rabeprazole to some extent. Based on the metabolic and pharmacokinetic differences among other proton pump inhibitors such as omeprazole, lansoprazole and pantoprazole, rabeprazole appears to be the least affected proton pump inhibitor by the CYP2C19‐related genetic polymorphism. Aim: To determine whether the pharmacodynamic effects of rabeprazole on intragastric pH and serum gastrin levels, and its pharmacokinetics depend on the CYP2C19 genotype status. Methods: Eighteen healthy subjects, whose CYP2C19 genotype status was previously determined, participated in the study. They consisted of six each of homozygous extensive metabolisers (homo EMs), heterozygous extensive metabolisers (hetero EMs), and poor metabolisers (PMs). Helicobacter pylori status was determined by serology. After a single oral dose of 10 mg or 20 mg rabeprazole or water only (baseline data), intragastric pH values were monitored for 24 h. Plasma levels of rabeprazole and serum gastrin were also measured for 24 h post‐dose. Results: Five homo EM, six hetero EM and four PM subjects were H. pylori‐negative. After rabeprazole administration, significant differences in intragastric mean pH values, serum gastrin AUC0–24 and plasma levels of rabeprazole were observed among the three different genotype groups. Conclusion: The pharmacodynamic effects of rabeprazole and its pharmacokinetics depend on the CYP2C19 genotype status.

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5-100 mg) and multiple (2.5-50 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (-18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (-29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite.

The concentration of landiolol hydrochloride rapidly reached steady state levels, and rapidly dissipated after completion of administration.