The Journal of pharmacy and pharmacology · 2026
Role of breast cancer resistance protein in pharmacokinetics of intrathecally administered methotrexate in mice.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Shintani Keiko, Nguyen Nguyet Kim, Ishimoto Takahiro, Itaya Ayuka, Yamamoto Yuya, Yamashita Reiya, Masuo Yusuke, Kato Yukio
Аннотация
OBJECTIVES: Intrathecal administration of methotrexate (MTX) is used to treat cancer in the central nervous system; however, it sometimes causes neurotoxicity. Despite their clinical importance, the pharmacokinetics and the mechanism underlying the neurotoxicity of intrathecally administered MTX are largely unknown. This study aimed to clarify the involvement of breast cancer resistance protein (BCRP) in the pharmacokinetics and neurotoxicity of intrathecally administered MTX.
METHODS: Plasma, brain, and cerebrospinal fluid (CSF) concentrations of MTX were compared between wild-type (WT) and Bcrp gene knockout mice. Choroid plexus (CP)-specific BCRP knockdown mice were constructed using adeno-associated virus encoding short hairpin RNA, and pharmacokinetic analysis and uptake studies in isolated CP were performed. Hippocampal neurogenesis was also evaluated.
KEY FINDINGS: Plasma and brain concentrations of intrathecally, but not intravenously administered MTX, were significantly higher in Bcrp gene knockout mice than in WT mice. Plasma MTX concentration was higher in CP-specific BCRP knockdown mice than in the control. BCRP inhibition enhanced MTX accumulation in isolated CP. MTX-induced decline in hippocampal cellular proliferation was exacerbated in Bcrp gene knockout mice.
CONCLUSIONS: BCRP may play an important role in MTX pharmacokinetics after intrathecal, but not intravenous, administration by regulating the CSF-to-blood transition in the CP and protecting against MTX-induced neurotoxicity.
METHODS: Plasma, brain, and cerebrospinal fluid (CSF) concentrations of MTX were compared between wild-type (WT) and Bcrp gene knockout mice. Choroid plexus (CP)-specific BCRP knockdown mice were constructed using adeno-associated virus encoding short hairpin RNA, and pharmacokinetic analysis and uptake studies in isolated CP were performed. Hippocampal neurogenesis was also evaluated.
KEY FINDINGS: Plasma and brain concentrations of intrathecally, but not intravenously administered MTX, were significantly higher in Bcrp gene knockout mice than in WT mice. Plasma MTX concentration was higher in CP-specific BCRP knockdown mice than in the control. BCRP inhibition enhanced MTX accumulation in isolated CP. MTX-induced decline in hippocampal cellular proliferation was exacerbated in Bcrp gene knockout mice.
CONCLUSIONS: BCRP may play an important role in MTX pharmacokinetics after intrathecal, but not intravenous, administration by regulating the CSF-to-blood transition in the CP and protecting against MTX-induced neurotoxicity.