Pharmacokinetics and bioavailability of midazolam after intravenous, subcutaneous, intraperitoneal and oral administration under a chronic food-limited regimen: relating DRL performance to pharmacokinetics

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Abstract
The effects of midazolam on animal behavior often are evaluated under a chronically food-limited regimen, which is used to implement food-reinforced performance, but the corresponding pharmacokinetics are lacking. The present study investigated the pharmacokinetics of midazolam after IV, SC, IP, and PO administration in food-limited rats. A two-compartment model best described the concentration-time profiles for the four routes of administration. The rate of midazolam absorption was rapid, and peak concentrations were attained in less than 7 min for the three extravascular routes. The mean volume of distribution of the central compartment and clearance were 0.77 l/kg and 2.03 l/h per kg, respectively. Midazolam elimination half-lives for the four routes of administration ranged from 23.1 to 49.5 min, and metabolites could not be detected. The mean absolute bioavailability was route-dependent: 39.3% (SC) 19.2% (IP) and 4.6% (PO). The markedly low oral bioavailability found in food-limited rats contrasted to the value reported for free-feeding rats (45%). Although the IP route yielded the highest maximum concentration on occasion, serum midazolam concentration-time profiles were variable, but did correspond to respective sedative responses. DRL 45-s performance after SC, IP, and PO administration further supported the advisability of using the SC route of administration, as opposed to the IP route, for studying midazolam dose-response relations. The bioavailability values assessed from DRL performance also agree with the measured pharmacokinetic values.