Impact of Solutol HS 15 on the pharmacokinetic behavior of midazolam upon intravenous administration to male Wistar rats.
The pharmacokinetic profile of midazolam (MDZ) and its major metabolites 1'-OH-midazolam (1'OH-MDZ) and 4-OH-midazolam (4OH-MDZ) was investigated in rats. MDZ was administered intravenously at 5 mg/kg either in the absence (NaCl 0.9%, control group) or in the presence of the surfactant Solutol HS 15, a weak inhibitor of cytochrome P450 3A (CYP3A) activity in vitro (Solutol HS 15-treated group). It was found that the pharmacokinetic profiles of MDZ, 1'OH-MDZ and 4OH MDZ did not differ significantly in the two dosing vehicles (P values above 0.2). MDZ exhibited a high plasma clearance (Cl) of 79 and 92 ml/min/kg (corresponding to a blood Cl of 64 and 75 ml/min/kg), a high volume of distribution (V(d)) of 4.0 and 3.6 l/kg, and an area under the plasma concentration-time curve (AUC(t0-tinf)) of 1062 and 932 h.ng/ml in the control group and in the Solutol HS 15-treated group, respectively. The amount of MDZ excreted unchanged into urine was below 0.01% with both dosing vehicles. AUC(t0-tinf) in the control group was 12.3 h.ng/ml for 1'OH-MDZ and 38.8 h.ng/ml 4OH-MDZ. In the Solutol HS 15-treated group, AUC(t0-tinf) was 14 h.ng/ml for 1'OH-MDZ and 35.4 h.ng/ml for 4OH-MDZ. The metabolite concentrations excreted into urine were below the limit of quantification. In the rat, MDZ has a high blood clearance that is limited by liver blood flow. Therefore, weak CYP3A inhibitors like Solutol HS 15 are not likely to affect the hepatic blood clearance of MDZ in vivo.
Bittner
Beate
B
Discovery DMPK, F. Hoffmann-La Roche Ltd., Basel, Switzerland. beate.bittner@roche.com
González
Roberto Carlos Bravo
RC
Isel
Hughes
H
Flament
Christophe
C
D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D006207:Half-Life; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013229:Stearic Acids / Q000494:pharmacology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D013997:Time Factors
D000277:Adjuvants, Pharmaceutic; D006993:Hypnotics and Sedatives; D013229:Stearic Acids; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; C067028:Solutol HS 15; D008874:Midazolam