Cossum P A, Dwyer K A, Roth M, Chen S A, Moffat B, Vandlen R, Ferraiolo B L
Department of Safety Evaluation, Genentech, Inc., South San Francisco, California 94080.
Pharm Res. 1992 Mar;9(3):419-24. doi: 10.1023/a:1015863507496.
The pharmacokinetics and tissue distribution of a human relaxin were investigated after intravenous (iv) bolus administration to pregnant or nonpregnant rats. Human gene-2 relaxin (hRlx-2) serum concentrations after iv bolus administration were described as the sum of three exponentials. The pharmacokinetics were comparable in pregnant and nonpregnant rats. The serum clearance (CL) was 7.4-10.2 ml/min/kg at doses of 46-93 micrograms/kg and was linear in this range. The half-lives were 1.1-2.0, 15.1-16.4, and 53.7-67.9 min, respectively. The volume of the central compartment (Vc) was 48-79 ml/kg and the volume of distribution at steady state (Vss) was 271-336 ml/kg. Increasing the dose to 463 micrograms/kg increased the dose-corrected area under the serum concentration-time curve and significantly decreased CL and Vss. The distribution of radioactivity in the tissues of pregnant rats was followed after iv bolus dosing with hRlx-2 internally labeled with 35S-cysteine. Comparison of the extent of organ uptake of radiolabel after 35S-hRlx-2 or 35S-cysteine administration suggested that the kidneys were the principal site of uptake; the liver was of secondary importance. In perfusion experiments utilizing livers isolated from pregnant or nonpregnant rats, 36-52% of the dose of hRlx-2 was cleared from the perfusate in 2 hr. These studies showed that the pharmacokinetics of hRlx-2 in rats appeared to be unaffected by pregnancy and suggested that the kidneys and liver both play a role in the elimination of hRlx-2.
在对怀孕或未怀孕的大鼠进行静脉推注给药后，研究了人松弛素的药代动力学和组织分布。静脉推注给药后人基因 -2 松弛素（hRlx-2）的血清浓度被描述为三个指数之和。怀孕和未怀孕大鼠的药代动力学具有可比性。在剂量为 46 - 93 微克/千克时，血清清除率（CL）为 7.4 - 10.2 毫升/分钟/千克，在此范围内呈线性。半衰期分别为 1.1 - 2.0、15.1 - 16.4 和 53.7 - 67.9 分钟。中央室容积（Vc）为 48 - 79 毫升/千克，稳态分布容积（Vss）为 271 - 336 毫升/千克。将剂量增加到 463 微克/千克会增加血清浓度 - 时间曲线下的剂量校正面积，并显著降低 CL 和 Vss。在用 35S - 半胱氨酸内部标记的 hRlx-2 进行静脉推注给药后，追踪了放射性在怀孕大鼠组织中的分布。比较 35S - hRlx-2 或 35S - 半胱氨酸给药后放射性在器官中的摄取程度表明，肾脏是主要摄取部位；肝脏的重要性次之。在利用从怀孕或未怀孕大鼠分离的肝脏进行的灌注实验中，2 小时内从灌注液中清除了 36 - 52%的 hRlx-2 剂量。这些研究表明，hRlx-2 在大鼠中的药代动力学似乎不受怀孕影响，并提示肾脏和肝脏在 hRlx-2 的消除中均起作用。
