Gardner Erin R, Burger Herman, van Schaik Ron H, van Oosterom Allan T, de Bruijn Ernst A, Guetens Gunther, Prenen Hans, de Jong Floris A, Baker Sharyn D, Bates Susan E, Figg William D, Verweij Jaap, Sparreboom Alex, Nooter Kees
Clinical Pharmacology Research Core, SAIC-Frederick, Frederick, USA.
Clin Pharmacol Ther. 2006 Aug;80(2):192-201. doi: 10.1016/j.clpt.2006.05.003.
Our objective was to explore the relationships between imatinib pharmacokinetics and 9 allelic variants in 7 genes coding for adenosine triphosphate-binding cassette transporters (ABCB1 and ABCG2) and enzymes (cytochrome P450 [CYP] 2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) of putative relevance for imatinib.
Imatinib transport in vitro was studied by use of human embryonic kidney 293 cells transfected with wild-type ABCG2 and an ABCG2 Q141K clone. Steady-state pharmacokinetics of imatinib was obtained in 82 patients with gastrointestinal stromal tumors treated with oral imatinib at doses ranging from 100 to 1000 mg/d. Genotyping was carried out via direct sequencing or restriction fragment length polymorphism-based techniques.
Human embryonic kidney 293 cells transfected with ABCG2 Q141K exhibited greater drug accumulation in vitro in comparison with cells expressing wild-type ABCG2 (P = .028). However, pharmacokinetic parameters of imatinib in vivo were not statistically significantly different in 16 patients who were heterozygous for ABCG2 421C>A compared with 66 patients carrying the wild-type sequence (P = .479). The apparent oral clearance of imatinib was potentially reduced in individuals with at least 1 CYP2D6*4 allele (median, 7.78 versus 10.6 L/h; P = .0695). Pharmacokinetic parameters were not related to any of the other multiple-variant genotypes (P >or= .230), possibly because of the low allele frequencies.
This study indicates that common genetic variants in the evaluated genes have only a limited impact on the pharmacokinetics of imatinib. Further investigation is required to quantitatively assess the clinical significance of homozygous variant ABCG2 and CYP2D6 genotypes in patients treated with imatinib.
我们的目的是探究伊马替尼药代动力学与7个基因中的9个等位基因变异之间的关系，这些基因编码与伊马替尼可能相关的三磷酸腺苷结合盒转运体（ABCB1和ABCG2）及酶（细胞色素P450 [CYP] 2C9、CYP2C19、CYP2D6、CYP3A4和CYP3A5）。
通过使用转染了野生型ABCG2和ABCG2 Q141K克隆的人胚肾293细胞来研究伊马替尼的体外转运。对82例接受口服伊马替尼治疗的胃肠道间质瘤患者进行稳态药代动力学研究，剂量范围为100至1000 mg/d。通过直接测序或基于限制性片段长度多态性的技术进行基因分型。
与表达野生型ABCG2的细胞相比，转染了ABCG2 Q141K的人胚肾293细胞在体外表现出更高的药物蓄积（P = 0.028）。然而，与66例携带野生型序列的患者相比，16例ABCG2 421C>A杂合子患者体内伊马替尼的药代动力学参数无统计学显著差异（P = 0.479）。至少携带1个CYP2D6*4等位基因的个体中，伊马替尼的表观口服清除率可能降低（中位数分别为7.78和10.6 L/h；P = 0.0695）。药代动力学参数与任何其他多变异基因型均无关联（P≥0.230），可能是由于等位基因频率较低。
本研究表明，所评估基因中的常见基因变异对伊马替尼药代动力学的影响有限。需要进一步研究以定量评估伊马替尼治疗患者中纯合变异ABCG2和CYP2D基因型的临床意义。
