2000 Fiscal Year Final Research Report Summary
Pharmacokinetics of ATRA in Pediatric Patients with Leukemia - Mechanism of Resistance to ATRA-
| Project/Area Number |
10470182
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Osaka Medical College |
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Principal Investigator |
TAMAI Hiroshi Faculty of Medicine, Osaka Medical College Professor, 医学部, 教授 (30179874)
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| 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)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Acute promyelocytic leukemia / Retinoic acid |
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| 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.
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