Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia: a collaborative Pediatric Oncology Branch, NCI, and Children's Cancer Group study
| Autor: | Robert F. Murphy, Linda C. Stork, Ray Hutchinson, Frank M. Balis, John S. Holcenberg, Bruce Bostrom, Elizabeth S. Lowe, Janet Franklin, Brenda J. Kitchen, Gregory H. Reaman, William Woods, Brigitte C. Widemann, Gary R. Erdmann, Peter C. Adamson |
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| Rok vydání: | 2001 |
| Předmět: |
Antimetabolites
Antineoplastic Cancer Research medicine.medical_specialty Erythrocytes medicine.medical_treatment Administration Oral Pilot Projects Toxicology Tioguanine Pharmacokinetics Acute lymphocytic leukemia Internal medicine Blood plasma medicine Humans Pharmacology (medical) Infusions Intravenous Thioguanine Chromatography High Pressure Liquid Pharmacology Chemotherapy business.industry Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Mercaptopurine Leukemia Endocrinology Oncology Area Under Curve Cerebrospinal fluid penetration business medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 47:199-205 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s002800000229 |
| Popis: | PURPOSE In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL. METHODS Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle. RESULTS After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46 +/- 0.68 microM and the AUC ranged from 0.18 to 9.5 microM.h (mean 1.5 microM.h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 microM, respectively. The mean (+/- SD) TG clearance was 935 +/- 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF. CONCLUSIONS TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG. |
| Databáze: | OpenAIRE |
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