| Backgroud: In the clinical setting, cerebrospinal fluid (CSF) levels of drugs are oftenused as evidence of delivery of drug to brain, even sometimes used as a surrogate fordrug concentrations at the target site within the brain to predict the CNS activity. Forbrain target sites in close contact with the ventricles, such as the meninges, ventricularCSF concentrations may be directly relevant. However, several microorganisms causingcentral nervous system infections are located principally in the brain extracellular fluid(bECF). In these cases, measurement of the anti-infective drugs concentrations in thecerebral extracellular fluid may be more important than measurement of drugconcentrations in cerebrospinal fluid. Since the CSF is a different fluid compartment tothe bECF，So the universality of the approach to regard the CSF level of drug as asurrogate for drug concentration at the target site needs further verification. Cerebralmicrodialysis is the only technique that enables us to directly sample molecules fromthe bECF. The continuous nature of microdialysis sampling of the ECF is ideal forpharmacokinetic (PK) studies.Objective: The purpose of the study is to investigate the penetration rate and thepharmacokinetics of voriconazole, praziquantel and moxifloxacin in cerebrospinal fluidand regional brain extracellular fluid compartments in rats， and to validate theuniversality of the approach to take the CSF level of drug as a surrogate for drugconcentration at the target site.Methods: Quantification of voriconazole (40mg/kg), praziquantel (150mg/kg) andmoxifloxacin (40mg/kg), three anti-infective agents commonly used in the treatment ofCSN infections, in CSF (the left lateral ventricle) and bECF (the right corpus striatum)after a single oral administration to rats were achieved by vivo microdialysis andhigh-performance liquid chromatographic method. The pharmacokinetic parameterswere analyzed by DAS2.0software. The penetration rate of durg in CSF and in bECF were defined as the ratio of AUCCSF/AUCplasmaand the the ratio of AUCbECF/AUCplasma,respectively. The difference in the pharmacokinetics and the penetration rate of theseanti-infective agents between in CSF and in bECF were compared.Results: After a single oral administration, the voriconazole concentration in the lateralventricle was found to be altered almost parallel with that in the striatum extracellularfluid. There was no significant difference in maximum concentration (Cmax), time topeak (Tmax)，traminal elimination half-life (T1/2), area under concentration-time curve(AUC0~∞) as well as the the penetration rate between in CSF and in bECF (P＞0.05).Similarly, the Cmax, Tmax, T1/2, AUC0~∞and the penetration rate of praziquantel werecomparable in CSF and in bECF (P＞0.05). Regarding to moxifloxacin, the TmaxandT1/2in the lateral ventricle was similar with that in the striatum (P＞0.05), however, theCmaxand AUC0~∞in the lateral ventricle (1.69±0.29μg/mL and17.93±1.77μg h/mL,respectively) were higher than those obtained in the striatum (0.92±0.11μg/mL and9.22±1.02μg h/mL, respectively)(P＜0.05). Moreover, the penetration rate ofmoxifloxacin in the lateral ventricle was higher than that obtained in the striatum (0.34±0.03,0.18±0.02)(P＜0.05).Conclusion: The in vivo microdialysis technique can be used for monitoring the levelsof voriconazole, praziquantel and moxifloxacin in CSF and bECF of rats. Thepharmacokinetics and penetration rates of the voriconazole and praziquantel in CSF andbECF of rats are similar, however, the pharmacokinetics of moxifloxacin in CSF andbECF are different and the penetration rate of moxifloxacin in the lateral ventricle washigher than that obtained in the striatum. For some anti-infective agents， thecorresponding bECF concentration could differ remarkably from the CSFconcentration，in this sense, the use of CSF concentrations alone to evaluate thepenetration of the blood-brain barrier by anti-infective agents and, therefore, to checktheir efficiency in the treatment of CNS infections may not be enough. |
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