Yoo Bo-Im, Ahan Kwang Bok, Kang Min Hee, Moon Dong-Cheul, Kwon Oh-Seung, Lee Hong Sub, Ryu Jung Su, Kim Tae Yong, Song Sukgil, Chung Youn Bok
National Research Laboratory (NRL) of PK/PD, Biotechnology Research Institute, College of Pharmacy, Chungbuk National University, Korea.
Biol Pharm Bull. 2005 Apr;28(4):688-93. doi: 10.1248/bpb.28.688.
We investigated the pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration in rats and beagle dogs. We developed an HPLC-based method to analyze ID-6105 levels in plasma, bile, urine, feces, and tissue homogenates and validated the method in a pharmacokinetic study. The plasma concentration of ID-6105 decreased to below the quantifiable limit (0.02 microg/ml) at 4 and 8 h after i.v. administration in rats at doses of 2 and 10 mg/kg, respectively (t(1/2,alpha) and t(1/2,beta) of 0.78 and 17.8 min at a dose of 2 mg/kg, 0.91 and 176 min at a dose of 10 mg/kg, respectively). The AUC increased with nonlinear pharmacokinetics following the dosage increase from 2 to 10 mg/kg in rats, while the pharmacokinetics were not significantly altered in beagle dogs following a dosage increase from 0.5 to 2.5 mg/kg. Of the various tissues tested, ID-6105 was mainly distributed in the lung, spleen, kidney, adrenal gland, and liver after i.v. bolus administration. ID-6105 levels in the lung or kidney 2 h after i.v. bolus administration were comparable to the initial plasma concentration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration became too small to measure. The cumulative amounts of ID-6105 found in the bile 48 h after the administration of 2 and 10 mg/kg were calculated to be 26.7 and 18.5% of the initial dose, respectively. The corresponding values in the urine 72 h after i.v. administration were 4.33 and 3.07% of the initial dose, suggesting that ID-6105 is mostly excreted in the bile. In conclusion, our observations indicate that ID-6105 was rapidly cleared from the blood and transferred to tissues such as the lung, spleen, kidney, and liver 2 h after i.v. bolus administration. Moreover, the majority of ID-6105 appears to be excreted in the bile by 24 h after i.v. bolus administration.
我们研究了新型蒽环类药物11 - 羟基阿克拉霉素X（ID - 6105）在大鼠和比格犬静脉推注给药后的药代动力学特征。我们开发了一种基于高效液相色谱的方法来分析血浆、胆汁、尿液、粪便和组织匀浆中的ID - 6105水平，并在药代动力学研究中验证了该方法。在大鼠中，静脉注射2和10 mg/kg剂量的ID - 6105后，血浆浓度分别在4和8小时降至可定量限以下（0.02 μg/ml）（2 mg/kg剂量时的t(1/2,α)和t(1/2,β)分别为0.78和17.8分钟，10 mg/kg剂量时分别为0.91和176分钟）。在大鼠中，随着剂量从2 mg/kg增加到10 mg/kg，AUC随非线性药代动力学增加，而在比格犬中，随着剂量从0.5 mg/kg增加到2.5 mg/kg，药代动力学没有显著改变。在测试的各种组织中，静脉推注给药后，ID - 6105主要分布在肺、脾、肾、肾上腺和肝脏中。静脉推注给药2小时后，肺或肾中的ID - 6105水平与初始血浆浓度相当。然而，静脉推注给药48小时后，各种组织中的ID - 6105浓度变得太小而无法测量。静脉注射2和10 mg/kg后48小时，胆汁中ID - 6105的累积量分别计算为初始剂量的26.7%和18.5%。静脉注射72小时后尿液中的相应值分别为初始剂量的4.33%和3.07%，表明ID - q105主要通过胆汁排泄。总之，我们的观察结果表明，静脉推注给药2小时后，ID - 6105迅速从血液中清除并转移到肺、脾、肾和肝脏等组织中。此外，静脉推注给药24小时后，大部分ID - 6105似乎通过胆汁排泄。
