Pharmacokinetics and pharmacodynamics of midazolam following intravenous and intramuscular administration to sheep.
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OBJECTIVE To determine the pharmacokinetic and pharmacodynamic effects of midazolam following IV and IM administration in sheep. ANIMALS 8 healthy adult rams. PROCEDURES Sheep were administered midazolam (0.5 mg/kg) by the IV route and then by the IM route 7 days later in a crossover study. Physiologic and behavioral variables were assessed and blood samples collected for determination of plasma midazolam and 1-hydroxymidazolam (primary midazolam metabolite) concentrations immediately before (baseline) and at predetermined times for 1,440 minutes after midazolam administration. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Following IV administration, midazolam was rapidly and extensively distributed and rapidly eliminated; mean SD apparent volume of distribution, elimination half-life, clearance, and area under the concentration-time curve were 838 330 mL/kg, 0.79 0.44 hours, 1,272 310 mL/h/kg, and 423 143 hng/mL, respectively. Following IM administration, midazolam was rapidly absorbed and bioavailability was high; mean SD maximum plasma concentration, time to maximum plasma concentration, area under the concentration-time curve, and bioavailability were 820 268 ng/mL, 0.46 0.26 hours, 1,396 463 hng/mL, and 352 148%, respectively. Respiratory rate was transiently decreased from baseline for 15 minutes after IV administration. Times to peak sedation and ataxia after IV administration were less than those after IM administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated midazolam was a suitable short-duration sedative for sheep, and IM administration may be a viable alternative when IV administration is not possible.
