Paradoxical relationship between acetylator phenotype and amonafide toxicity
- PMID: 1934870
- DOI: 10.1038/clpt.1991.183
Paradoxical relationship between acetylator phenotype and amonafide toxicity
Abstract
Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration-time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.
Similar articles
-
Individualized dosing of amonafide based on a pharmacodynamic model incorporating acetylator phenotype and gender.Pharmacogenetics. 1996 Feb;6(1):93-101. doi: 10.1097/00008571-199602000-00008. Pharmacogenetics. 1996. PMID: 8845865
-
Phase I study of amonafide dosing based on acetylator phenotype.Cancer Res. 1993 May 15;53(10 Suppl):2304-8. Cancer Res. 1993. PMID: 8485716 Clinical Trial.
-
Population pharmacodynamic study of amonafide: a Cancer and Leukemia Group B study.J Clin Oncol. 1995 Mar;13(3):741-7. doi: 10.1200/JCO.1995.13.3.741. J Clin Oncol. 1995. PMID: 7884434 Clinical Trial.
-
Genetically determined variability in acetylation and oxidation. Therapeutic implications.Drugs. 1985 Apr;29(4):342-75. doi: 10.2165/00003495-198529040-00003. Drugs. 1985. PMID: 2859977 Review.
-
Acetylation.Birth Defects Orig Artic Ser. 1990;26(1):43-65. Birth Defects Orig Artic Ser. 1990. PMID: 2224079 Review.
Cited by
-
Is body composition an important variable in the pharmacokinetics of anticancer drugs? A review and suggestions for further research.Cancer Chemother Pharmacol. 1994;34(1):3-13. doi: 10.1007/BF00686105. Cancer Chemother Pharmacol. 1994. PMID: 8174199 Review. No abstract available.
-
Amonafide treatment of refractory esophageal cancer. A Southwest Oncology Group study.Invest New Drugs. 1993 Feb;11(1):47-51. doi: 10.1007/BF00873910. Invest New Drugs. 1993. PMID: 8349435 Clinical Trial.
-
Benefits of pharmacological knowledge in the design and monitoring of cancer chemotherapy.Pathol Oncol Res. 1998;4(3):171-8. doi: 10.1007/BF02905246. Pathol Oncol Res. 1998. PMID: 9761935 Review.
-
Statistical approaches to pharmacodynamic modeling: motivations, methods, and misperceptions.Cancer Chemother Pharmacol. 1993;33(1):1-9. doi: 10.1007/BF00686015. Cancer Chemother Pharmacol. 1993. PMID: 8269582 Review.
-
UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA-MB-231 cells.Exp Ther Med. 2018 Nov;16(5):3921-3928. doi: 10.3892/etm.2018.6675. Epub 2018 Sep 3. Exp Ther Med. 2018. PMID: 30344670 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
