Pharmacokinetics of ATRA in Pediatric Patients with Leukemia - Mechanism of Resistance to ATRA-

ATRA 在儿童白血病患者中的药代动力学 - ATRA 耐药机制 -

• 批准号: 10470182
• 负责人: TAMAI Hiroshi
• 金额: $ 3.26万
• 依托单位: Osaka Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470182/
• 关键词: Acute promyelocytic leukemia; Retinoic acid

All-transretinoic acid (ATRA) has attracted much attention since it was found to induce complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). The effectiveness of ATRA for APL is reported to be related to the plasma or serum levels achieved after administration. A pharmacokinetic study of ATRA was undertaken in nine patients with various leukemias. After oral administration at a dose of 30 mg/m^2, the time required to reach the peak plasma level of ATRA (20 - 1,198 ng/ml) was between 120 and 240 min and the apparent plasma elimination half life was 21 - 51 min.ATRA therapy did not induce complete remission in all patients, even when high plasma levels were achieved. Among the six APL patients receiving ATRA therapy, one who failed to respond had a very low plasma ATRA level. These findings suggest that it may be useful to monitor plasma levels during oral ATRA therapy in order to achieve an appropriate treatment regimen.The pharmacokinetics of ATRA and 4-oxo all-transretinoic acid (4-oxo ATRA), a metabolite of ATRA, were studied in four children with APL at the time of initial oral administration. After administration of ATRA at a dose of 30 mg/m^2, the peak plasma ATRA level was 20 - 741 ng/ml and was reached at 60 - 120 min. The patient with the lowest peak plasma level did not achieve complete remission and had a very high 4-oxo ATRA level compared to the patients with complete remission. These findings suggest that accelerated metabolism of ATRA plays a role in the failure of this agent in the patients without remission.

全反式维甲酸（ATRA）因其可诱导大部分急性早幼粒细胞白血病（APL）患者完全缓解而备受关注。据报道，ATRA 对 APL 的有效性与给药后达到的血浆或血清水平有关。在 9 名患有各种白血病的患者中进行了 ATRA 的药代动力学研究。口服30 mg/m^2剂量后，达到ATRA血浆峰值水平（20 - 1,198 ng/ml）所需的时间为120至240分钟，表观血浆消除半衰期为21 - 51 min.ATRA 治疗并未使所有患者完全缓解，即使达到高血浆水平也是如此。在接受 ATRA 治疗的 6 名 APL 患者中，一名没有反应的 APL 患者血浆 ATRA 水平非常低。这些研究结果表明，在口服 ATRA 治疗期间监测血浆水平可能有助于实现适当的治疗方案。ATRA 和 4-氧代全反式维甲酸 (4-oxo ATRA)（ATRA 的一种代谢物）的药代动力学是对四名首次口服给药时患有 APL 的儿童进行了研究。以30 mg/m^2的剂量施用ATRA后，血浆ATRA水平峰值为20 - 741 ng/ml，并在60 - 120分钟时达到。与完全缓解的患者相比，血浆峰值水平最低的患者没有达到完全缓解，并且 4-oxo ATRA 水平非常高。这些发现表明，ATRA 代谢加速是该药物在未缓解的患者中失败的原因之一。