Klawitter Jost, Easton Mckay, Karpeisky Alexander, Farrell Kristen B, Thamm Douglas H, Shokati Touraj, Christians Uwe, Zinnen Shawn Patrick
Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Psychiatry, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Molecules. 2025 Jan 16;30(2):354. doi: 10.3390/molecules30020354.
The use of the bone-seeking properties of bisphosphonates (BPs) to target the delivery of therapeutic drugs is a promising approach for the treatment of bone metastases. Currently, the most advanced example of this approach is a gemcitabine-ibandronate conjugate (GEM-IB), where the bone-targeting BP ibandronate (IB) is covalently linked to the antineoplastic agent gemcitabine (GEM) via a spacer phosphate group. In the present study, we describe the development of a new analytical platform to evaluate the metabolism and pharmacokinetics of GEM-IB in mice and dogs and the results of proof-of-concept studies assessing the pharmacokinetics of GEM-IB in dogs and mice.
We validated analytical platforms to analyze GEM-IB and five of its major metabolites IB, gemcitabine-5'-phosphate (GEMMP), gemcitabine (GEM), 2',2'-difluoro-2'-deoxyuridine-5'-phosphate (dFdUMP), and 2',2'-difluoro-2'-deoxyuridine (dFdU) and performed proof-of-concept pharmacokinetic studies in mice (5 mg/kg i.p.) and dogs (5 mg/kg i.v.).
Intra- and inter-run accuracy and imprecision (3 days) of the assays met the (FDA) acceptance criteria. The proof-of-concept plasma pharmacokinetic studies in mice showed AUCs of 1278, 10,652, 405, 38, 1063, 3389, and 38 h·ng/mL for GEM-IB, IB, GEMMP, dFdU-MP, GEM, and dFdU, respectively. In dog plasma, AUCs of 295, 5725, 83, 11, 1625, and 6569 h·ng/mL were observed for GEM-IB, IB, GEMMP, dFdUMP, GEM, and dFdU.
Pharmacokinetic studies in dogs and mice showed that GEM-IB is rapidly converted to IB and GEM; dFdU is formed (from GEM) with a delay. The rapid disappearance of GEM-IB from circulation could be explained by a combination of metabolism and rapid distribution to tissue/bone.
利用双膦酸盐（BP）的亲骨特性来靶向递送治疗药物是治疗骨转移的一种有前景的方法。目前，这种方法最先进的例子是吉西他滨 - 伊班膦酸共轭物（GEM - IB），其中骨靶向性双膦酸盐伊班膦酸（IB）通过间隔磷酸基团与抗肿瘤药物吉西他滨（GEM）共价连接。在本研究中，我们描述了一种新的分析平台的开发，用于评估GEM - IB在小鼠和犬体内的代谢和药代动力学，以及评估GEM - IB在犬和小鼠体内药代动力学的概念验证研究结果。
我们验证了用于分析GEM - IB及其五种主要代谢物IB、吉西他滨 - 5'-磷酸（GEMMP）、吉西他滨（GEM）、2',2'-二氟 - 2'-脱氧尿苷 - 5'-磷酸（dFdUMP）和2',2'-二氟 - 2'-脱氧尿苷（dFdU）的分析平台，并在小鼠（腹腔注射5 mg/kg）和犬（静脉注射5 mg/kg）中进行了概念验证药代动力学研究。
各分析方法的批内和批间准确性及不精密度（3天）均符合（美国食品药品监督管理局）FDA的验收标准。在小鼠中进行的概念验证血浆药代动力学研究显示，GEM - IB、IB、GEMMP、dFdU - MP、GEM和dFdU的曲线下面积（AUC）分别为1278、10652、405、38、1063、3389和38 h·ng/mL。在犬血浆中，GEM - IB、IB、GEMMP、dFdUMP、GEM和dFdU的AUC分别为295、5725、83、11、1625和6569 h·ng/mL。
在犬和小鼠中进行的药代动力学研究表明，GEM - IB迅速转化为IB和GEM；dFdU（由GEM形成）的形成有延迟。GEM - IB从循环中迅速消失可通过代谢和快速分布到组织/骨骼的综合作用来解释。
