Abstract
The clinical pharmacokinetics of midazolam have been extensively studied, due to its high clearance by CYP3A4 and sensitivity to drug–drug interactions. In order to investigate the potential to model drug–drug interactions with midazolam in the dog, a selective and sensitive high performance liquid chromatography-tandem mass spectroscopy (HPLC-MS-MS) method has been developed, with sufficient sensitivity to allow analysis of dog plasma samples generated following administration of a clinically relevant dose. The method involves extraction of midazolam and internal standard (flunitrazepam) from dog plasma, using 96-well Oasis ® MCX solid phase extraction plates. The assay has been validated over a concentration range of 0.1–10 ng/ml and its specificity, accuracy and precision demonstrated. The relative bias of the assay was within ±15% for all standards with intra- and inter-assay precision (coefficient of variation—%CV) of less than 15%. The assay was applied to the analysis of plasma samples (0.2 ml), generated following intravenous or oral administration of midazolam to male beagle dogs, at a dose level of 0.05 mg/kg, and pharmacokinetic parameters were derived from the resulting data.
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