McKillop D, Partridge E A, Hutchison M, Rhead S A, Parry A C, Bardsley J, Woodman H M, Swaisland H C
Drug Metabolism and Pharmacokinetics Department, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Xenobiotica. 2004 Oct;34(10):901-15. doi: 10.1080/00498250400009189.
The pharmacokinetics of gefitinib and its metabolites in rat and dog were investigated in preclinical studies conducted to support the safety evaluation and clinical development of gefitinib, the first EGFR tyrosine kinase inhibitor approved for the treatment of non-small-cell lung cancer. Following intravenous dosing (5 mg kg(-1), gefitinib plasma half-life was 3-6h in rats and dogs, although studies using a more sensitive HPLC-MS assay produced longer estimates of half-life (7-14h). In these studies, plasma clearance was high (male rat: 25 ml min(-1) kg(-1); female rat: 16 ml min(-1) kg(-1); male dog: 16 ml min(-1) kg(-1)), as was the volume of distribution (8.0-10.41 kg(-1) in rat; 6.31 kg(-1) in dog), and exposure in female rats was double that in males. Following administration of [14C]-gefitinib, concentrations of radioactivity in plasma exceeded gefitinib throughout the profile, indicating the presence of circulating metabolites in both rat and dog. An HPLC-MS assay was developed to measure concentrations of gefitinib and five potential metabolites in plasma. All five metabolites were detected in the rat, but at levels much lower than gefitinib. In the dog, exposure to gefitinib and M523595 was similar, with much lower concentrations of M537194 and only trace levels of the other metabolites. This profile of metabolites is similar to that observed in man.
在支持吉非替尼安全性评估和临床开发的临床前研究中，对吉非替尼及其代谢产物在大鼠和犬体内的药代动力学进行了研究。吉非替尼是首个被批准用于治疗非小细胞肺癌的表皮生长因子受体酪氨酸激酶抑制剂。静脉给药（5 mg·kg⁻¹）后，吉非替尼在大鼠和犬体内的血浆半衰期为3 - 6小时，不过使用更灵敏的高效液相色谱 - 质谱分析法进行的研究得出的半衰期估计值更长（7 - 14小时）。在这些研究中，血浆清除率较高（雄性大鼠：25 ml·min⁻¹·kg⁻¹；雌性大鼠：16 ml·min⁻¹·kg⁻¹；雄性犬：16 ml·min⁻¹·kg⁻¹），分布容积也较高（大鼠为8.0 - 10.4 l·kg⁻¹；犬为6.3 l·kg⁻¹），雌性大鼠体内的暴露量是雄性大鼠的两倍。给予[¹⁴C] - 吉非替尼后，整个过程中血浆中的放射性浓度均超过吉非替尼浓度，表明大鼠和犬体内均存在循环代谢产物。开发了一种高效液相色谱 - 质谱分析法来测定血浆中吉非替尼和五种潜在代谢产物的浓度。在大鼠体内检测到了所有五种代谢产物，但水平远低于吉非替尼。在犬体内，吉非替尼和M523595的暴露量相似，M537194的浓度低得多，其他代谢产物仅为痕量水平。这种代谢产物谱与在人体内观察到的相似。
