Madu A, Cioffe C, Mian U, Burroughs M, Tuomanen E, Mayers M, Schwartz E, Miller M
Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York.
Antimicrob Agents Chemother. 1994 Sep;38(9):2111-5. doi: 10.1128/AAC.38.9.2111.
Complete concentration-time data describing the pharmacokinetics of fluconazole in the cerebrospinal fluid (CSF) following a single dose are not available for humans or animals. We studied the pharmacokinetics of fluconazole with an indwelling intracisternal needle as described by R.G. Dacey and M.A. Sande (Antimicrob. Agents Chemother. 6:437-441, 1974). To determine whether the presence of an intracisternal needle alters pharmacokinetics in the CSF, we validated this model with uninfected rabbits by measuring pharmacokinetic constants following direct intracisternal and intravenous administration of fluconazole. Following direct injection, there was no alteration of elimination rates in the CSF with increasing sample number or time. Following intravenous administration, the penetration and kinetic constants were the same in individual animals from which multiple CSF samples were obtained as in a composite subject constructed by pooling virgin samples from different animals. The presence of the intracisternal needle did not alter CSF chemistry or leukocyte counts, and erythrocyte contamination was < 0.001%. While drug concentrations were measured by a microbiological assay, we also compared the sensitivity and reproducibility of a high-performance liquid chromatography (HPLC) assay with those of the microbiological assay. Following a single intravenous dose, the maximum concentration of the drug in serum, the time to maximum concentration of the drug in serum, the terminal elimination half-life in the CSF, and the percent penetration by fluconazole were 6.12 micrograms/ml, 1 h, 9.0 h, and 84.3%, respectively. We conclude that the sampling of CSF via an indwelling needle does not alter fluconazole pharmacokinetics, cause inflammation, or alter chemical parameters; that the microbiological assay is at least equivalent in sensitivity and reproducibility to the HPLC assay; and that robust parameters describing the pharmacokinetics of fluconazole are possible with this model.
目前尚无完整的描述单剂量氟康唑在人体或动物脑脊液（CSF）中药代动力学的浓度-时间数据。我们采用了R.G. 达西和M.A. 桑德（《抗菌剂与化疗》6:437 - 441, 1974）所描述的留置脑池内针的方法研究了氟康唑的药代动力学。为了确定脑池内针的存在是否会改变CSF中的药代动力学，我们通过测量氟康唑直接脑池内给药和静脉给药后的药代动力学常数，在未感染的兔子身上验证了该模型。直接注射后，CSF中的消除率不会随着样本数量或时间的增加而改变。静脉给药后，在获得多个CSF样本的个体动物中，其渗透和动力学常数与通过汇集来自不同动物的原始样本构建的复合受试者相同。脑池内针的存在并未改变CSF的化学成分或白细胞计数，红细胞污染率<0.001%。虽然药物浓度是通过微生物学测定法测量的，但我们还比较了高效液相色谱（HPLC）测定法与微生物学测定法的灵敏度和重现性。单次静脉给药后，血清中药物的最大浓度、血清中药物达到最大浓度的时间、CSF中的终末消除半衰期以及氟康唑的渗透百分比分别为6.12微克/毫升、1小时、9.0小时和84.3%。我们得出结论，通过留置针采集CSF不会改变氟康唑的药代动力学、引起炎症或改变化学参数；微生物学测定法在灵敏度和重现性方面至少与HPLC测定法相当；并且使用该模型可以获得描述氟康唑药代动力学的可靠参数。
