Peters G J, Clavel M, Noordhuis P, Geyssen G J, Laan A C, Guastalla J, Edzes H T, Vermorken J B
Department of Medical Oncology, VU University Medical University, Amsterdam, The Netherlands.
J Chemother. 2007 Apr;19(2):212-21. doi: 10.1179/joc.2007.19.2.212.
Gemcitabine (dFdC) was tested in a Phase I trial at 14 doses (40-5700 mg/m(2)), administered every 2 weeks as a (1/2) -h infusion to 52 patients with refractory solid cancer. Gemcitabine and its deaminated metabolite difluorodeoxyuridine (dFdU), measured with HPLC, reached plasma peak levels of 2-3 microM at 40 mg/m(2) which increased to 512 microM at 5700 mg/m(2). Gemcitabine was eliminated rapidly with a t(1/2) beta of 2.3-15.8 min in the 40-5700 mg/m(2) dose range, with one exception of 38 min at 4500 mg/m(2) . dFdU was still present at a plateau of +/- 20 microM from 4-24 h at doses >960 mg/m(2). Up to 3650 mg/m(2) linear pharmacokinetics were observed for gemcitabine, while those for dFdU were linear over the whole range. Gemcitabine clearance varied between 1.5-12.6 l/min and was 1.5-fold higher in males than in females (p= 0.024); its volume of distribution was 45.2-248 l. In lymphocytes peak levels of the active metabolite dFdCTP were 100-380 pmol/10( 6 )cells in the first course. Apparently a plateau was reached which was confirmed by incubation of white blood cells with increasing gemcitabine concentrations up to 500 microM, reaching a plateau of about 350 pmol/10(6 )cells; in contrast in cancer cells this concentration dependence did not exist and accumulation reached about 1590 pmol/10( 6 )cells. In tumors isolated from patients treated with gemcitabine dFdCTP reached about 70 pmol/g wet weight. Gemcitabine itself was eliminated only to a limited extent in the urine, but dFdU was eliminated almost completely in the urine in the first 24 h (51-92%). In conclusion, dFdC was rapidly eliminated in contrast to dFdU, which was present for at least 18 h, as well as dFdCTP in lymphocytes.
吉西他滨（dFdC）在一项I期试验中对14种剂量（40 - 5700mg/m²）进行了测试，每2周给药一次，以1/2小时静脉输注的方式给予52例难治性实体癌患者。用高效液相色谱法测定，吉西他滨及其脱氨基代谢产物二氟脱氧尿苷（dFdU）在40mg/m²时血浆峰值水平达到2 - 3μM，在5700mg/m²时升至512μM。在40 - 5700mg/m²剂量范围内，吉西他滨快速消除，β半衰期为2.3 - 15.8分钟，4500mg/m²时为38分钟是唯一例外。在剂量>960mg/m²时，dFdU在4 - 24小时内维持在±20μM的平台期。吉西他滨在高达3650mg/m²时呈现线性药代动力学，而dFdU在整个范围内均呈线性。吉西他滨清除率在1.5 - 12.6l/min之间，男性比女性高1.5倍（p = 0.024）；其分布容积为45.2 - 248l。在第一个疗程中，淋巴细胞中活性代谢产物dFdCTP的峰值水平为100 - 380pmol/10⁶细胞。显然达到了一个平台期，这通过将白细胞与高达500μM的递增吉西他滨浓度孵育得到证实，达到约350pmol/10⁶细胞的平台期；相比之下，在癌细胞中不存在这种浓度依赖性，积累量达到约1590pmol/10⁶细胞。在接受吉西他滨治疗的患者分离出的肿瘤中，dFdCTP达到约70pmol/g湿重。吉西他滨本身仅在尿液中有限程度地消除，但dFdU在前24小时内几乎完全在尿液中消除（51 - 92%）。总之，与至少存在18小时的dFdU以及淋巴细胞中的dFdCTP相比，dFdC快速消除。
