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首页> 外文期刊>Journal of Translational Medicine >The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism
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The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

机译：血浆醛固酮和尿钠钾比作为盐皮质激素受体拮抗作用的可翻译定量生物标志物的应用

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Background Accumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra?), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound. Methods The effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans. Results In Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na+/K+ yielding an EC50 that was within 5-fold of the functional in vitro IC50. More importantly, the effect of eplerenone on urinary Na+/K+ in healthy volunteers yielded an EC50 that was within 2-fold of the EC50 generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na+/K+ in Sprague-Dawley rats was within 3-fold of its in vitro functional potency. The effect of MR antagonism on urinary Na+/K+ was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC50 values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion. Importantly, similar unbound concentrations of eplerenone in humans and SHR rats yielded the same magnitude of elevations in aldosterone, indicating a good translatability from rat to human. Conclusions Urinary Na+/K+ and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively. Trial Registration For clinical study reference EE3-96-02-004, this study was completed in 1996 and falls out scope for disclosure requirements. Clinical study reference A6141115: http://clinicaltrials.gov webcite , http://NIHclinicaltrails.gov webcite ; NCTID: NCT00990223
机译：背景技术越来越多的证据支持盐皮质激素受体（MR）在糖尿病性肾病发病机理中的作用。这些发现引起了人们对新型MR拮抗剂的新兴趣，该拮抗剂具有提高的对其他核激素受体的选择性并可能降低高钾血症的风险。新型MR拮抗剂的表征可确保在MR受体上建立活性的可翻译生物标记。我们使用依普利酮（Inspra ？）评价了尿钠钾比（Na + / K + ）和血浆醛固酮作为MR拮抗作用的生物标志物的可翻译性>），市售MR拮抗剂。此外，我们利用这些生物标记物证明了新型化合物PF-03882845对MR的拮抗作用。方法表征依普利农和PF-03882845对Sprague-Dawley大鼠和自发性高血压大鼠（SHR）尿Na + / K + 和血浆醛固酮的影响。另外，在健康志愿者中确定依普利农对这些生物标志物的作用。对药物暴露反应数据进行建模，以评估这些生物标记物从大鼠到人类的可翻译性。结果在Sprague-Dawley大鼠中，依普利农对尿中Na + / K + 产生的EC 50 迅速升高了5倍以内。功能性体外IC 50 的功能。更重要的是，依匹乐酮对健康志愿者尿中Na + / K + 的作用产生的EC 50 约为其的2倍。在Sprague-Dawley大鼠中产生EC 50 。同样，PF-03882845在Sprague-Dawley大鼠中提高尿Na + / K + 的能力在其体外功能能力的3倍以内。 MR拮抗作用对尿Na + / K + 的作用不是长期持续的。因此，我们在SHR中长期给药后研究了这些化合物对血浆醛固酮的影响。对依普利农和PF-03882845的药物暴露-响应数据进行建模，得出的EC 50 值在根据药物暴露随尿中钠和钾排泄量变化估算的值的2倍以内。重要的是，在人类和SHR大鼠中类似的未结合依匹乐酮浓度会导致醛固酮升高幅度相同，表明从大鼠到人的翻译性良好。结论尿Na + / K + 和血浆醛固酮分别是单剂或多剂给药后MR拮抗作用的可翻译生物标志物。试用注册对于参考EE3-96-02-004的临床研究，该研究于1996年完成，属于披露要求的范围。临床研究参考文献A6141115：http://clinicaltrials.gov网站，http://NIHclinicaltrails.gov网站; NCTID：NCT00990223

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