| Autor: |
Philip, Sandoval, Bei-Ching, Chuang, John K, Fallon, Philip C, Smith, Swapan K, Chowdhury, Robert J, Griffin, Cindy Q, Xia, Shinji, Iwasaki, Paresh P, Chothe |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
The AAPS journal. 24(6) |
| ISSN: |
1550-7416 |
| Popis: |
The liver is central to the elimination of many drugs from the body involving multiple processes and understanding of these processes is important to quantitively assess hepatic clearance of drugs. The synthetic STING (STimulator of INterferon Genes protein) agonist is a new class of drugs currently being evaluated in clinical trials as a potential anticancer therapy. In this study, we used ML00960317 (synthetic STING agonist) to investigate the hepatobiliary disposition of this novel molecular entity. A bile-duct cannulated (BDC) rat study indicated that biliary excretion is the major route of elimination for ML00960317 (84% of parent dose in bile). The human biliary clearance using in vitro sandwich cultured human hepatocyte model predicted significant biliary excretion of ML00960317 (biliary excretion index (BEI) of 47%). Moreover, the transport studies using transporter expressing cell lines, hepatocytes, and membrane vesicles indicated that ML00960317 is a robust substrate of OATP1B1, OATP1B3, and MRP2. Using relative expression factor approach, the combined contribution of OATP1B1 (fraction transported (f |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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