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

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 i.v., s.c., i.p., and p.o. administration in food-limited rates. 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 keg, 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% (s.c.) 19.2% (i.p.) and 4.6% (p.o.). The markedly low oral bioavailability found in food-limited rats contrasted to the value reported for free-feeding rates (45%). Although the i.p. 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 s.c., i.p., and p.o. administration further supported the advisability of using the s.c. route of administration, as opposed to the i.p. route, for studying midazolam dose-response relations. The bioavailability values assessed from DRL performance also agree with the measured pharmacokinetic values.

In Vitro, Pharmacokinetic, and Pharmacodynamic Interactions of Ketoconazole and Midazolam in the Rat

“…Consistent with previous studies (Mandema and Danhof, 1992;Lau et al, 1996;Higashikawa et al, 1999a,b,c;Laurijssens and Greenblatt, 2002), clearance of intravenously administered midazolam in rats was high, with a mean control clearance value (without inhibitor) of 79 ml/min/kg. Intragastric midazolam had a mean net bioavailability of only 11%.…”

Effect of hyperlipidemia on ketoconazole–midazolam drug–drug interaction in rat

“…28 Oral dosing of KTZ was chosen to maximize KTZ liver uptake, wherein the drug would first pass through the liver during entry to the systemic circulation. The study design also matched well with other experimental designs previously reported in literature having an average time interval between the two doses ranging from 0.5 to 2 h. [28][29][30][31] The CL of MDZ in NL rats (Table 1) was similar to previous reports, [29][30][31][32] although the t 1 2 appeared to be longer. The underlying reason behind may be that in the current study, MDZ was measured for up to 8 h after i.v.…”

Aminoglutethimide, a corticosteroid synthesis inhibitor, facilitates brain stimulation reward in food-restricted rats: an investigation of underlying mechanisms

“…Starvation is known to affect microsomal enzymes (Ma et al 1989) and thereby alter the bioavailability of hexobarbital (Sachan 1982), midazolam (Lau et al 1996) and other drugs (Ma et al 1989). Food restriction may also increase CNS entry of AG and metabolites by opening the blood-brain barrier.…”