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
Hillman Cancer Research Center, Molecular Therapeutics Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Invest New Drugs. 2006 Sep;24(5):393-401. doi: 10.1007/s10637-006-6335-5.
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 ABCG2 on the pharmacokinetic disposition of 9NC and 9AC.
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 ABCG2 genes. The ABCB1 1236C>T (n = 43), ABCB1 2677G>T/A (n = 43), ABCB1 3435C>T (n = 43), ABCC2 3972C>T (n = 39), and ABCG2 421C>A (n = 42) variants were analyzed using Pyrosequencing.
The ABCG2 421C>A genotype 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 x h and 51.1 ng/mL x 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 x h and 129.0 +/- 90.5 ng/mL x h, respectively (P = 0.40). 9NC and 9AC disposition were not significantly influenced by variants in ABCB1, ABCC2, and ABCG2, and ABCB1 and ABCC2, respectively (P > 0.05).
These findings suggest that inter-individual variability in 9AC disposition, but not 9NC, may be influenced, in part, by ABCG2 genotype. In contrast, there was no evidence for a relationship between ABCG2 and the disposition of 9NC, or for relationships between ABCB1 and ABCC2 genotypes and the disposition of 9NC or 9AC.
9-硝基喜树碱（9NC）及其9-氨基喜树碱（9AC）代谢物的药代动力学变异性来源尚不清楚。据报道，ATP结合盒（ABC）转运蛋白可调节喜树碱类似物，与喜树碱耐药性相关，也可能影响9NC和9AC的药代动力学。本研究的目的是评估转运蛋白基因ABCB1、ABCC2和ABCG2中已知单核苷酸多态性对9NC和9AC药代动力学处置的功能影响。
作为9NC在难治性实体瘤患者中的两项I期研究、9NC在晚期结肠癌患者中的II期研究以及一项评估禁食条件下单剂量给药后9NC处置情况的研究的一部分，对55例患者进行了药代动力学和基因分型研究。从血浆中分离DNA，并分析ABCB1、ABCC2和ABCG2基因中的变异。使用焦磷酸测序分析ABCB1 1236C>T（n = 43）、ABCB1 2677G>T/A（n = 43）、ABCB1 3435C>T（n = 43）、ABCC2 3972C>T（n = 39）和ABCG2 421C>A（n = ）变异。
ABCG2 421C>A基因型显著影响9AC的药代动力学。野生型（n = 25）和杂合子（n = 2）患者的9AC内酯AUC/剂量平均值分别为14.3 ng/mL×h和51.1 ng/mL×h（P = 0.032）。野生型（n = 39）和杂合子（n = 3）患者的9AC总AUC/剂量平均值分别为91.9±78.3 ng/mL×h和129.0±90.5 ng/mL×h（P = 0.40）。ABCB1、ABCC2和ABCG2以及ABCB1和ABCC2中的变异分别对9NC和9AC的处置没有显著影响（P > 0.05）。
这些发现表明，9AC处置的个体间变异性（而非9NC）可能部分受ABCG2基因型影响。相比之下，没有证据表明ABCG2与9NC的处置之间存在关系，也没有证据表明ABCB1和ABCC2基因型与9NC或9AC的处置之间存在关系。
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