Nakayama Y, Furuta Y, Watanabe Y, Inoue T, Kurono M
Pharmaceutical Laboratory, Sanwa Kagaku Kenkyusho Company, Ltd., Mie, Japan.
J Pharm Sci. 1996 Nov;85(11):1238-41. doi: 10.1021/js950488f.
Plasma concentrations of human urinary kininogenase (HUK) were determined in healthy volunteers during and after intravenous (iv) infusion by enzyme immunoassay (EIA). Plasma kinin concentrations were also determined by radioimmunoassay (RIA), and related to HUK concentrations. When HUK was infused [at 0.04, 0.075, 0.15, and 0.3 p-nitroaniline unit (PNAU)/body] over 30 min, plasma HUK concentration rapidly increased and reached a maximum at the end of dosing. Then, the concentration of HUK in plasma decreased biexponentially, and the elimination half-life of the terminal phase was found to be approximately 170 min. The area under the curve of concentration versus time from 0 to 180 min (AUC0-180min) and the maximum concentration (Cmax) increased in proportion to the dose, whereas the pharmacokinetic parameters [mean residense time (MRTinf) = 200-270 min, plasma clearance (CLp) = 2.5-3.3 mL/min/kg, volume of distribution at steady state (Vdss) = 470-730 mL/kg] did not very significantly within the dose range of the present study. On the other hand, when HUK was infused (at 0.15 PNAU/body), plasma kinin concentrations reached approximately 2 ng of bradykinin eq/mL 15 min after the onset of administration. This concentration was maintained during the dosing period, after which kinin was rapidly eliminated, and its concentration returned to baseline at 10 min after dose withdrawal. Plasma kinin concentrations at 15 to 30 min after the onset of dosing (at 0.075, 0.15, and 0.3 PNAU/body) increased in proportion to the dose. The pharmacokinetic parameters of HUK (MRTinf, CLp, Vdss) were compared with those of rats, rabbits, and dogs (log-log plots of body weight versus MRTinf, CLp, and Vdss). The Vdss value showed a good correlation (r = 0.996 for n = 4) with the body weight of respective animal species, the correlation with CLp was weak (r = 0.911), and MRTinf did not exhibit any correlation.
通过酶免疫测定法（EIA）测定了健康志愿者在静脉输注期间及之后人尿激肽原酶（HUK）的血浆浓度。血浆激肽浓度也通过放射免疫测定法（RIA）进行了测定，并与HUK浓度相关联。当以0.04、0.075、0.15和0.3对硝基苯胺单位（PNAU）/体重的剂量在30分钟内输注HUK时，血浆HUK浓度迅速升高，并在给药结束时达到最大值。然后，血浆中HUK的浓度呈双指数下降，发现终末相的消除半衰期约为170分钟。从0至180分钟的浓度-时间曲线下面积（AUC0-180min）和最大浓度（Cmax）与剂量成正比增加，而在本研究的剂量范围内，药代动力学参数[平均驻留时间（MRTinf）= 200 - 270分钟，血浆清除率（CLp）= 2.5 - 3.3 mL/分钟/千克，稳态分布容积（Vdss）= 470 - 730 mL/千克]变化不是非常显著。另一方面，当以0.15 PNAU/体重的剂量输注HUK时，给药开始后15分钟血浆激肽浓度达到约2 ng缓激肽当量/毫升。该浓度在给药期间维持，之后激肽迅速消除，停药后10分钟其浓度恢复至基线。给药开始后15至30分钟（剂量为0.075、0.15和0.3 PNAU/体重）的血浆激肽浓度与剂量成正比增加。将HUK的药代动力学参数（MRTinf、CLp、Vdss）与大鼠、兔子和狗的参数进行了比较（体重与MRTinf、CLp和Vdss的对数-对数图）。Vdss值与各动物物种的体重显示出良好的相关性（n = 4时r = 0.996），与CLp的相关性较弱（r = 0.911），而MRTinf未显示出任何相关性。
