In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepa m were examined in chronically instrumented sheep via measurements of their after io-venous concentration difference across the brain during and after 2-min iv infusions. Diazepam (30 mg) or min'azolam (10 mg), were administe red on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral upta ke occurred during the infusion, which quickly turned to elution in the pos tinfusion period. However; this process was more rapid for midazolam than d iazepam. The cerebral pharmacokinetics of both was better described by a ki netic model with slight membrane limitation, rather than flow limitation. F or diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 mi n, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. lit a subset of sheep, pulmonary arterial-arterial gradients were too small to measure suggesting limited metabolism and small distribut ion volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral bloodflow and algesimetry lagged behind both the arterial and s agittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13 .3 and 5.5 min for midazolam and diazepam, respectively). Effect compartmen t modeling of the cerebral bloodflow data showed apparent effect compartmen t half-lives (t(1/2,keo)) that were longer than the half-lives of cerebral equilibration.