Disposition of 9-nitrocamptothecin and its 9-aminocamptothecin metabolite in relation to ABC transporter genotypes

Autor: Zamboni, William C., Ramanathan, Ramesh K., McLeod, Howard L., Mani, Sridhar, Potter, Douglas M., Strychor, Sandra, Maruca, Lauren J., King, Cristi R., Jung, Laura L., Parise, Robert A., Egorin, Merrill J., Davis, Todd A., Marsh, Sharon
Zdroj: Investigational New Drugs; September 2006, Vol. 24 Issue: 5 p393-401, 9p
Abstrakt: Purpose: The source of the pharmacokinetic variability of 9-nitrocamptothecin (9NC) and its 9-aminocamptothecin (9AC) metabolite is unknown. ATP-binding cassette (ABC) transporters have been reported to modulate camptothecin analogues, are associated with camptothecin resistance, and might also affect 9NC and 9AC pharmacokinetics. The aim of this study was to evaluate the functional consequence of known single nucleotide polymorphisms in the transporter genes ABCB1, ABCC2, and ABCG2on the pharmacokinetic disposition of 9NC and 9AC. Experimental design: Pharmacokinetic and genotyping studies were performed in 55 patients as part of two phase I studies of 9NC in patients with refractory solid tumors, a phase II study of 9NC in patients with advanced colon cancer, and a study evaluating the disposition of 9NC after administration of a single dose under fasting conditions. DNA was isolated from plasma and analyzed for variants in ABCB1, ABCC2, and ABCG2genes. The ABCB11236C>T (n= 43), ABCB12677G>T/A(n= 43), ABCB13435C>T (n= 43), ABCC23972C>T (n= 39), and ABCG2421C>A(n= 42) variants were analyzed using Pyrosequencing. Results: The ABCG2421C>Agenotype significantly affected the pharmacokinetics of 9AC. The mean 9AC lactone AUC/dose for wild-type (n= 25) and heterozygous (n= 2) patients were 14.3 ng/mL · h and 51.1 ng/mL. h, respectively (P= 0.032). The mean ± SD 9AC total AUC/dose for wild-type (n= 39) and heterozygous (n= 3) patients were 91.9 ± 78.3 ng/mL · h and 129.0 ± 90.5 ng/mL · h, respectively (P= 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1and ABCC2, respectively (P>0.05). Conclusion: These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2genotype. In contrast, there was no evidence for a relationship between ABCG2and the disposition of 9NC, or for relationships between ABCB1and ABCC2genotypes and the disposition of 9NC or 9AC.
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