Meffin P J, Sallustio B C, Purdie Y J, Jones M E
J Pharmacol Exp Ther. 1986 Jul;238(1):280-7.
The disposition of 2-phenylpropionic acid (2PPA) enantiomers has been studied in 12 rabbits with normal renal function (control) and in 6 rabbits with renal dysfunction. In control animals a mean (S.E.M.) of 0.23 (0.02) of R-2PPA was inverted to S-2PPA, and the distribution volumes for unbound S- and R-2PPA were 0.30 (0.02) and 0.62 (0.07) liters/kg, respectively, but there was no evidence of stereoselectivity in the glucuronidation of R- or S-2PPA. A model was developed that predicted the fraction of the 2PPA in plasma present as unbound S-2PPA upon infusion of racemic 2PPA to steady state. The mean (S.E.M.) observed fraction was 0.69 (0.01) and the predicted fraction was 0.66 (0.03). Comparing the mean parameters of 2PPA disposition in renal dysfunction with those in the same animals during a control study, the fraction of R-2PPA undergoing inversion increased by 350%, the clearance of unbound S-2PPA decreased to 25% and the unbound clearance of R-2PPA by processes other than inversion decreased to 9% of the control means. These changes are consistent with the effects of renal dysfunction on acyl-glucuronide futile cycles for both R- and S-2PPA. Using the above data it can be calculated that, in an animal with severe renal dysfunction, upon an infusion of racemic 2PPA to steady state the concentration of the unbound S-enantiomer would be 5.6 times that in a control animal.
在12只肾功能正常的兔子（对照组）和6只肾功能不全的兔子中研究了2-苯丙酸（2PPA）对映体的处置情况。在对照动物中，平均（标准误）有0.23（0.02）的R-2PPA转化为S-2PPA，未结合的S-和R-2PPA的分布容积分别为0.30（0.02）和0.62（0.07）升/千克，但在R-或S-2PPA的葡萄糖醛酸化过程中没有立体选择性的证据。建立了一个模型，该模型预测在输注外消旋2PPA至稳态后血浆中以未结合S-2PPA形式存在的2PPA的比例。观察到的平均（标准误）比例为0.69（0.01），预测比例为0.66（0.03）。将肾功能不全时2PPA处置的平均参数与同一动物在对照研究中的参数进行比较，发生转化的R-2PPA的比例增加了350%，未结合S-2PPA的清除率降至25%，除转化外其他过程导致的未结合R-2PPA的清除率降至对照平均值的9%。这些变化与肾功能不全对R-和S-2PPA的酰基葡萄糖醛酸无效循环的影响一致。利用上述数据可以计算出，在一只患有严重肾功能不全的动物中，在输注外消旋2PPA至稳态后，未结合S-对映体的浓度将是对照动物的5.6倍。
