Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.
Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients.
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发表时间：
2003
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通讯作者：
C. Gambacorti-Passerini;M. Zucchetti;D. Russo;R. Frapolli;M. Verga;S. Bungaro;L. Tornaghi;F. Rossi;P. Pioltelli;E. Pogliani;D. Alberti;G. Corneo;M. D’Incalci
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作者：
C. Gambacorti-Passerini;M. Zucchetti;D. Russo;R. Frapolli;M. Verga;S. Bungaro;L. Tornaghi;F. Rossi;P. Pioltelli;E. Pogliani;D. Alberti;G. Corneo;M. D’Incalci
伊马替尼（Glivec）是一种有效的bcr/abl抑制剂，bcr/abl是一种引起慢性髓性白血病（CML）的致癌融合蛋白。在动物模型中，α 1酸性糖蛋白（AGP）以高亲和力与伊马替尼结合，并抑制伊马替尼的体外和体内活性。对CML患者进行了伊马替尼的药代动力学分析。实验设计测量19例接受伊马替尼治疗（400或600 mg/天）的CML患者的伊马替尼血浆浓度。5例患者同时接受克林霉素短期疗程（CLI）。结果AGP与伊马替尼血浆水平呈正相关。CLI给药降低了伊马替尼血浆浓度，以曲线下面积（AUC）和峰值浓度（C(max)）来评估。在最后一次伊马替尼给药23小时后，研究了3例患者服用CLI的效果。3例患者中有3例在5-10分钟内，CLI导致伊马替尼血药浓度分别下降2.6倍、2.7倍和4.7倍。利用CML患者的新鲜细胞进行的体外实验表明，在患者体内观察到的浓度下，AGP可将伊马替尼细胞内浓度降低10倍，并阻断伊马替尼的活性。CLI孵育恢复伊马替尼细胞内浓度和生物活性。结论AGP对CML患者伊马替尼的药代动力学、血药浓度和细胞内分布有显著影响；这些数据表明，血浆伊马替尼水平代表该分子细胞浓度的不可靠指标。
PURPOSE Imatinib (Glivec) is a potent inhibitor of bcr/abl, an oncogenic fusion protein that causes chronic myelogenous leukemia (CML). alpha1 acid glycoprotein (AGP) binds to imatinib with high affinity and inhibits imatinib activity in vitro and in vivo in an animal model. A pharmacokinetics analysis of imatinib was undertaken in CML patients. EXPERIMENTAL DESIGN Imatinib plasma concentrations were measured in 19 CML patients treated with imatinib (400 or 600 mg/day). Five patients received a concomitant short-term course of clindamycin (CLI). RESULTS A positive correlation between AGP and imatinib plasma levels was observed. CLI administration decreased imatinib plasma concentrations, evaluated as area under the curve (AUC) and peak concentrations (C(max)). The effects of a bolus of CLI was studied in three patients on imatinib 23 h after the last imatinib dose. Within 5-10 min in three of three cases, CLI caused a decrease in imatinib plasma concentrations of 2.6-, 2.7-, and 4.7-fold, respectively. In vitro experiments using fresh blasts from CML patients showed that AGP, at concentrations observed in the patients, decreased imatinib intracellular concentrations up to 10 times and blocked imatinib activity. The incubation with CLI restored imatinib intracellular concentrations and biological activity. CONCLUSION AGP exerts significant effects of the pharmacokinetics, plasma concentrations, and intracellular distribution of imatinib in CML patients; these data indicate that plasma imatinib levels represent unreliable indicators of the cellular concentrations of this molecule.