In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.

摘要: Factors influencing the rate and extent of benzodiazepine uptake into cerebrospinal fluid (CSF), peripheral tissue distribution electroencephalographic (EEG) effects were evaluated in a model utilizing anesthetized male cats. A single (0.25-10 mg/kg) dose following eight benzodiazepines was administered i.v.: diazepam, desmethyldiazepam, midazolam, lorazepam, alprazolam, triazolam, flunitrazepam clobazam. Multiple samples simultaneously drawn from arterial blood cisternal CSF over next 4 hr EEG continuously monitored. Concentrations plasma measured by electron-capture gas-liquid chromatography protein binding determined equilibrium dialysis. Physicochemical properties lipophilicity each measurement octanol/buffer partition ratio at physiologic pH high-pressure liquid chromatographic (HPLC) retention on reverse-phase C18 column neutral pH. Disappearance all consistent with linear sum two or three exponential terms. After correction for individual differences binding, volume (Vd) unbound drug highly correlated HPLC (r = 0.91), but not significantly related to coefficient. Diazepam having longest also had largest Vd. All rapidly entered CSF, peak concentrations usually attained within 15 min dosage. More lipophilic drugs tended enter most rapidly, associations entry vitro significant. attained, disappearance both occurred parallel. Equilibrium CSF/total concentration ratios much less than unity.(ABSTRACT TRUNCATED AT 250 WORDS)