Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer
Autor: | Juan J. Marugan, Samarjit Patnaik, Udo Rudloff, Noel Southall, Debra Gilbert, Sui Huang, Chen Wang, Zachary Knotts, Christopher R. Dextras, Amy Wang, Stephanie Springer, Serguei Kozlov, Catherine Drennan, Marc Ferrer, Tomas Vilimas, Theresa Guerin, Kevin J. Frankowski, Jerome J. Schlomer, Emma Hughes, Marc D. Singleton, Xin Xu, Dandan Li |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Hepatocyte Nuclear Factor 3-alpha Cancer Research Cmax Administration Oral Antineoplastic Agents Mice Transgenic Pharmacology Toxicology KPC mice 03 medical and health sciences Mice 0302 clinical medicine Pharmacokinetics Pancreatic cancer Cell Line Tumor medicine Animals Humans Pharmacology (medical) Pyrroles Tissue Distribution Metarrestin Volume of distribution Organelles Perinucleolar compartment Dose-Response Relationship Drug Chemistry Forkhead Transcription Factors Peri-nucleolar compartment (PNC) medicine.disease 3. Good health Bioavailability Mice Inbred C57BL Pancreatic Neoplasms 030104 developmental biology Pyrimidines Oncology Pharmacodynamics Organ Specificity 030220 oncology & carcinogenesis Area Under Curve Cancer cell Injections Intravenous Original Article Half-Life |
Zdroj: | Cancer Chemotherapy and Pharmacology |
ISSN: | 1432-0843 0344-5704 |
Popis: | Purpose Metarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers. Methods PK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice. Results Metarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors. Conclusions Metarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery. Electronic supplementary material The online version of this article (10.1007/s00280-018-3699-0) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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