Midkine (MK) is a heparin-binding growth factor that functions in multiple physiological processes, making it a promising drug target for treating various diseases including osteoarthritis (OA). However, the lack of pharmacokinetic studies on MK limits further clinical research. As the N-domain of MK protein appears to be more important for its stability, this study aimed to investigate the pharmacokinetic profiles of recombinant human (rh)MK with different structures at the N-terminus via different administration routes in rats and guinea pigs. A single intramuscular (IM) injection of 1 mg/kg rhMK with or without extended sequences at the N-terminus expressed by E. coli or Pichia was administered to six male SD rats. rhMK concentrations in sequential tail blood samples were measured by ELISA. rhMK without extended N-terminal sequences expressed by Pichia had a greater area under the curve (AUC), slower clearance, and longer half-life in rats following a single IM injection than those of the other rhMK proteins. The AUC values for rhMK after IM and intra-articular (IA) administration were 1523.3 ± 35.2 h × ng/mL and 872.0 ± 36.1 h × ng/mL, whereas the apparent volumes of distribution (Vd/f) were 0.184 ± 0.067 L/kg and 11.6 ± 0.8 L/kg, respectively, suggesting that rhMK was distributed more locally after IA injection than after IM injection as Vd/f magnitude gives a general idea of extent distribution in the body and higher Vd/f represents more locally distribution. rhMK concentration in the articular cartilage was markedly higher than that in serum and reached the highest level at 3 days after a single IA injection in Hartley guinea pigs. As the dose increased from 10 to 50 mg/kg, the AUC increased in a greater-than-dose-proportional manner, suggesting that rhMK exhibits non-linear pharmacokinetics in rats after a single IM injection in this dose range. These results indicated that the N-terminal structure and administration route have substantial effects on the pharmacokinetics of rhMK in rats. Furthermore, rhMK was maintained in articular cartilage with minimal diffusion into the blood following IA injection in Hartley guinea pigs, providing a foundation for clinical research on the use of rhMK for OA treatment via IA delivery.

中文翻译：

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具有不同N端结构的Midkine在大鼠中的药代动力学。

Midkine（MK）是一种肝素结合生长因子，在多种生理过程中起作用，使其成为治疗包括骨关节炎（OA）在内的各种疾病的有希望的药物靶标。然而，缺乏关于MK的药代动力学研究限制了进一步的临床研究。由于MK蛋白的N结构域似乎对其稳定性更重要，因此本研究旨在研究通过不同给药途径在大鼠和豚鼠中在N末端具有不同结构的重组人（rh）MK的药代动力学概况。对六只雄性SD大鼠进行1毫克/千克rhMK的单次肌内（IM）注射，在大肠杆菌或毕赤酵母表达的N端带有或不带有扩展序列。通过ELISA测量连续尾血样品中的rhMK浓度。与其他rhMK蛋白相比，在单次IM注射后大鼠中，无毕赤酵母表达的无扩展N端序列的rhMK具有更大的曲线下面积（AUC），较慢的清除率和更长的半衰期。IM和关节内（IA）给药后rhMK的AUC值为1523.3±35.2 h×ng / mL和872.0±36.1 h×ng / mL，而表观分布体积（Vd / f）为0.184±0.067 L / kg和11.6±0.8 L / kg，分别表明IA注射后rhMK比IM注射后更局部分布，因为Vd / f幅值给出了体内范围分布的一般概念，而更高的Vd / f代表了更局部的分布。在Hartley豚鼠单次IA注射后第3天，关节软骨中的rhMK浓度显着高于血清中的rhMK浓度，并达到最高水平。当剂量从10 mg / kg增加到50 mg / kg时，AUC以大于剂量的比例增加，这表明在此剂量范围内单次IM注射后rhMK在大鼠中表现出非线性药代动力学。这些结果表明，N端结构和给药途径对大鼠rhMK的药代动力学有实质性影响。此外，在注射Hartley豚鼠后，rhMK保持在关节软骨中，扩散到血液中的可能性最小，这为使用rhMK通过IA递送进行OA治疗的临床研究奠定了基础。AUC以大于剂量比例的方式增加，这表明在此剂量范围内单次IM注射后，rhMK在大鼠中表现出非线性药代动力学。这些结果表明，N端结构和给药途径对大鼠rhMK的药代动力学有实质性影响。此外，在注射Hartley豚鼠后，rhMK保持在关节软骨中，扩散到血液中的可能性最小，这为使用rhMK通过IA递送进行OA治疗的临床研究奠定了基础。AUC以大于剂量比例的方式增加，这表明在此剂量范围内单次IM注射后，rhMK在大鼠中表现出非线性药代动力学。这些结果表明，N端结构和给药途径对大鼠rhMK的药代动力学有实质性影响。此外，在注射Hartley豚鼠后，rhMK保持在关节软骨中，扩散到血液中的可能性最小，这为使用rhMK通过IA递送进行OA治疗的临床研究奠定了基础。