Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs
Background. 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-...
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2025-01-01
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| author | Jost Klawitter Mckay Easton Alexander Karpeisky Kristen B. Farrell Douglas H. Thamm Touraj Shokati Uwe Christians Shawn Patrick Zinnen |
| author_facet | Jost Klawitter Mckay Easton Alexander Karpeisky Kristen B. Farrell Douglas H. Thamm Touraj Shokati Uwe Christians Shawn Patrick Zinnen |
| author_sort | Jost Klawitter |
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| description | Background. 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. Methods. 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.). Results. 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. Conclusions. 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. |
| format | Article |
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| institution | Kabale University |
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| publishDate | 2025-01-01 |
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| spelling | doaj-art-dfaa65c9b6774582b696d3d4753b77e42025-01-24T13:43:44ZengMDPI AGMolecules1420-30492025-01-0130235410.3390/molecules30020354Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and DogsJost Klawitter0Mckay Easton1Alexander Karpeisky2Kristen B. Farrell3Douglas H. Thamm4Touraj Shokati5Uwe Christians6Shawn Patrick Zinnen7Department of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USAMBC Pharma Inc., Aurora, CO 80045, USAFlint Animal Cancer Center, Colorado State University, Fort Collins, CO 80523, USAFlint Animal Cancer Center, Colorado State University, Fort Collins, CO 80523, USADepartment of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Anesthesiology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USAMBC Pharma Inc., Aurora, CO 80045, USABackground. 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. Methods. 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.). Results. 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. Conclusions. 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.https://www.mdpi.com/1420-3049/30/2/354bisphosphonatesbone cancerpharmacokineticsgemcitabine ibandronatehigh-performance liquid chromatographymass spectrometry |
| spellingShingle | Jost Klawitter Mckay Easton Alexander Karpeisky Kristen B. Farrell Douglas H. Thamm Touraj Shokati Uwe Christians Shawn Patrick Zinnen Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs Molecules bisphosphonates bone cancer pharmacokinetics gemcitabine ibandronate high-performance liquid chromatography mass spectrometry |
| title | Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs |
| title_full | Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs |
| title_fullStr | Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs |
| title_full_unstemmed | Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs |
| title_short | Novel Approaches to Monitor Pharmacokinetics and Metabolism of Gemcitabine-Ibandronate Conjugate in Mice and Dogs |
| title_sort | novel approaches to monitor pharmacokinetics and metabolism of gemcitabine ibandronate conjugate in mice and dogs |
| topic | bisphosphonates bone cancer pharmacokinetics gemcitabine ibandronate high-performance liquid chromatography mass spectrometry |
| url | https://www.mdpi.com/1420-3049/30/2/354 |
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