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

Research Project

Project/Area Number10470182
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionOsaka Medical College

Principal Investigator

TAMAI Hiroshi  Faculty of Medicine, Osaka Medical College Professor, 医学部, 教授 (30179874)

Co-Investigator(Kenkyū-buntansha) TAKITANI Kimitaka  Faculty of Medicine, Osaka Medical College Research associate, 医学部, 助手 (80319540)
MIYAKE Munenori  Faculty of Medicine, Osaka Medical College Research associate, 医学部, 助手 (10268203)
Project Period (FY) 1998 – 2000
Project Status Completed(Fiscal Year 2000)
Budget Amount *help
¥5,100,000 (Direct Cost : ¥5,100,000)
Fiscal Year 2000 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1999 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 1998 : ¥2,900,000 (Direct Cost : ¥2,900,000)
KeywordsAcute promyelocytic leukemia / Retinoic acid
Research Abstract

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.

Report

(4results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report

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Published : 1998-04-01   Modified : 2016-04-21  

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