title: A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice.
abstract: The hepatic cytochrome P450 reductase null (HRN) mouse, which has no functional hepatic Cyp P450s, may represent a useful model for examining extra-hepatic P450-related oxidative metabolism. Here the pharmacokinetics and metabolic fate of midazolam, a drug known to undergo such extra-hepatic metabolism, have been investigated in the HRN mouse and compared with a phenotypically normal strain (C57BL/6J). In addition, the effects of co-administration of the pan-P450 inhibitor 1'-aminobenzotriazole (ABT) on the metabolic profile have been compared in both strains. Significant pharmacokinetic differences for midazolam were observed between the two strains of mice with the HRN mice showing lower circulating concentrations of 1'-hydroxymidazolam but higher concentrations of 1'-hydroxymidazolam-O-glucuronide. A significant increase in midazolam exposure was seen upon ABT exposure for both strains of mice, but no differences in the area under the concentration time curves (AUC) for the monitored metabolites were observed. Although oxidative metabolism of midazolam was not abolished, significant decreases in 1'-hydroxymidazolam formation ratios were observed for both strains of mice exposed to ABT. Metabolite profiling of blood and bile showed a number of qualitative and quantitative differences between HRN and normal mice. These differences in midazolam metabolism between the two strains of mice clearly demonstrate the role that liver P450 enzymes play in the murine metabolism of midazolam. The fate of the compound in the HRN mice shows the importance of extrahepatic metabolism and also showed that these mice appear to be more capable of forming circulating phase II glucuronides than the normal strain.
authors.affiliation: Global DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Aidan
authors.initials: A
authors.lastname: Grimsley
authors.affiliation: Drug Safety and Metabolism, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Foster
authors.affiliation: Oncology iMed DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Gallagher
authors.affiliation: Global DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchison
authors.affiliation: RIA iMed DMPK, AstraZeneca Sweden, Pepparedsleden 1, 43183, Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Lundqvist
authors.affiliation: Oncology iMed DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Pickup
authors.affiliation: Global DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Wilson
authors.affiliation: Global DMPK, AstraZeneca UK Ltd., Alderley Park, Macclesfield, SK10 4TG, United Kingdom; RIA iMed DMPK, AstraZeneca Sweden, Pepparedsleden 1, 43183, Mölndal, Sweden. Electronic address: samuelsson.kristin@gmail.com.
authors.forename: Kristin
authors.initials: K
authors.lastname: Samuelsson
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008874:Midazolam / Q000493:pharmacokinetics*; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism*
chemical_list: D006993:Hypnotics and Sedatives; D009251:NADPH-Ferrihemoprotein Reductase; D008874:Midazolam
keywords: ABT; HRN; In vitro; In vivo; Midazolam