Abstract
To determine whether the pharmacokinetics of 6-mercaptopurine (6-MP) would show dose dependency, we studied three different single oral doses in eight children (aged 3.6 to 15.1 years) with acute leukemia in remission. Marked interindividual differences in maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were observed when children received the 50 mg/m2 dose. This variability decreased when the doses were increased. Six of the eight children showed a disproportionate increase in the AUC with increasing doses; the other two had a proportionate relationship between the AUC and dose. Overall mean (±SD) Cmax and AUC values increased disproportionately (88±123, to 326±194, to 653±344 ng/ml for Cmax, and 147±180, to 451±177, to 1291±415 ng/ml per hour for AUC, respectively) when the dose increased from 50 to 87.5 mg/m2 and then to 175 mg/m2. The results suggest that a saturable first-pass metabolism of oral 6-MP occurs with increasing oral doses in some, but not all, children. Whether and to what extent this pharmacokinetic character of oral 6-MP affects the interindividual difference in systemic exposure to the drug in children with leukemia receiving maintenance therapy require further studies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 311-316 |
| Number of pages | 6 |
| Journal | The Journal of pediatrics |
| Volume | 119 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 1991 |
Funding
6-Mercaptopurine is one of the standard agents for the treatment of children with acute lymphocytic leukemia in remission.i, 2 Despite a success rate of about 90% in inducing remission in children with acute lymphocytic leukemia, 30% to 40% of such children have relapses. 1 Previous investigators 3"6 have shown that the bioavailability of oral 6-MP was unexpectedly low and highly variable among persons receiving this drug. For instance, Zimm et al. 3 found that an average of 16% of the dose was bioavailable and that the interindividual variability ranged from 5% to Supported by research grants for Pediatric Research (63-A-03) and Cancer Research (1-9) from the Ministry of Human Health and Welfare, Tokyo, Japan. Submitted for publication April 12, 1990; accepted Feb. 13, 1991. Reprint requests: Takashi Ishizaki, MD, PhD, Clinical Research Institute, National Medical Center, Toyama 1-21-2, Shinjuku-ku, Tokyo 162, Japan. 9/25/28995 37% after an oral dose of 75 mg/m 2, suggesting that children receiving similar doses of oral 6-MP per unit of body size may be exposed systemically to considerably different amounts. The low and variable bioavailability of the drug
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
