期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 78, 期 6, 页码 1225-1235出版社
SPRINGER
DOI: 10.1007/s00280-016-3181-9
关键词
Pharmacokinetics; Small molecule inhibitor of STAT3; IL-6; LC-MS
资金
- Federal Funds from National Cancer Institute, National Institutes of Health [HSN261200800001E]
- NExT-CBC [1015, S08-221]
- NCI Chemical Biology Consortium
- Pittsburgh Specialized Application Center (PSAC)
- University of Pittsburgh Chemical Diversity Center
- American Cancer Society
- Head and Neck Spore P50 award [CA097190]
- National Cancer Institute, National Institutes of Health under Chemical Biology Consortium [HSN261200800001E]
- [P30CA047904]
Purpose The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination. Methods Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single-dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing, and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined. Results Of the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% Solutol T was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was similar to 5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro. Conclusions Rapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.
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