A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice

Grimsley, Aidan; Foster, Alison J.; Gallagher, Richard T.; Hutchison, Michael; Lundqvist, Anders; Pickup, Kathryn; Wilson, Ian D.; Samuelsson, Kristin

doi:10.1016/j.bcp.2014.10.004

Cited by 8 publications

(3 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HRN mouse only has residual hepatic P450 activity as a result of a liver-specific knockout of the P450 reductase enzyme during the postnatal period (Henderson et al, 2003), and extrahepatic P450 is unaffected. Marked differences in drug disposition have been observed in HRN mice compared with wild-type mice (Pickup et al, 2012;Boggs et al, 2014;Grimsley et al, 2014). After a single bolus dose of ABT to mice, the duration of inhibitory activity was relatively short: clearance of antipyrine was restored between 8 and 24 hours after inhibitor administration.…”

mentioning

confidence: 99%

Application of Osmotic Pumps for Sustained Release of 1-Aminobenzotriazole and Inhibition of Cytochrome P450 Enzymes in Mice: Model Comparison with the Hepatic P450 Reductase Null Mouse

Stringer

Ferreira

Rose

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

The effectiveness of controlled release 1-aminobenzotriazole (ABT) administration to inhibit cytochrome P450 (P450) enzymes has been evaluated in mice. To maximize the duration of P450 inhibition in vivo, ABT was administered via an osmotic pump. The degree of P450 inhibition was compared with that achieved with a single bolus dose of ABT. Two-hour prior subcutaneous treatment of mice with ABT (50 mg/kg) inhibited antipyrine clearance by 88%. A less pronounced inhibitory effect (29% reduction in clearance) was observed when ABT was administered 24-hours before antipyrine administration, indicating partial restoration of P450 activity during this longer pretreatment time. The duration of ABT in mice was very short (mean residence time = 1.7 hours) after subcutaneous bolus administration. When the inhibitor was delivered by an osmotic pump, maximum blood concentrations of the inhibitor were observed 24 hours after device implantation and were maintained at steady state for 6 days. Inhibition of P450 activity, as measured by antipyrine clearance, was confirmed at 24 hours and 120 hours after pump implantation, highlighting the utility of this method as a longerterm model for P450 inhibition in mice. The magnitude of P450 inhibition in ABT-treated mice was compared with that in hepatic P450 reductase null mice and both models were comparable. In vivo ABT administration by an osmotic pump offers an effective approach for longer-term P450 inhibition in mice and avoids the necessity for multiple dosing of the inhibitor. Introduction1-Aminobenzotriazole (ABT) is a time-dependant inhibitor of cytochrome P450 (P450) enzymes (Ortiz de Montellano et al., 1984) and is often used as a tool compound for in vitro (Furnes and Schlenk, 2005) and in vivo (Stringer et al., 2014;Boily et al., 2015) drug metabolism studies. The utility of ABT for in vivo P450 inhibition has been evaluated in a range of species, including mice, rats, guinea pigs, dogs, and monkeys (Balani et al., 2002(Balani et al., , 2004. For each species, efficient inhibition of metabolism was demonstrated with antipyrine, a nonspecific substrate of P450 enzymes (Engel et al., 1996;Sharer and Wrighton, 1996). To avoid the need for repeated ABT administration, we have explored the use of osmotic pumps as a technology to achieve sustained release of ABT and sustained inhibition of P450 enzymes in mice.To assess the effectiveness of the in vivo ABT approach, we compared the degree of P450 inhibition using this method with that in the hepatic reductase null (HRN) mouse. The HRN mouse only has residual hepatic P450 activity as a result of a liver-specific knockout of the P450 reductase enzyme during the postnatal period (Henderson et al., 2003), and extrahepatic P450 is unaffected. Marked differences in drug disposition have been observed in HRN mice compared with wild-type mice (Pickup et al., 2012;Boggs et al., 2014;Grimsley et al., 2014). After a single bolus dose of ABT to mice, the duration of inhibitory activity was relatively short: clearance of antipyrin...

show abstract

mentioning

confidence: 99%

Application of Osmotic Pumps for Sustained Release of 1-Aminobenzotriazole and Inhibition of Cytochrome P450 Enzymes in Mice: Model Comparison with the Hepatic P450 Reductase Null Mouse

Stringer

Ferreira

Rose

et al. 2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…Group 5 mice were orally treated with 100 mg/kg/day of ABT (dissolved in 0.3 % CMC-Na solution) for 2 days and then treated orally with 4.5 mg/kg cantharidin 0.5 h after the last administration of ABT (Grimsley et al, 2014). Group 6 and group 7 mice received an oral dose of 4.5 mg/kg cantharidin or coin oil, respectively.…”

Section: Stability Studies and Liver Microsomal Incubationsmentioning

confidence: 99%

Covalent Binding of Reactive Anhydride of Cantharidin to Biological Amines

Fan,

Chen,

Jing

et al. 2024

Drug Metab Dispos

View full text Add to dashboard Cite

Cantharidin is a terpenoid from coleoptera beetles. Cantharidin has been used to treat molluscum contagiosum and some types of tumors. Cantharidin is highly toxic and cantharidin poisoning and fatal cases have been reported worldwide. The mechanisms underlying cantharidin-induced toxicity remain unclear. Cantharidin contains anhydride, which may react with biological amines. This study aimed to examine the chemical reactivity of cantharidin toward nucleophiles and characterize adducts of cantharidin with biological amines in vitro and in mice. Here, two types of conjugates were formed in the incubation of cantharidin under physiologic conditions with free amino acids, a mimic peptide, or amine-containing compounds, respectively. Amide-type conjugates were produced by the binding of cantharidin anhydride with the primary amino group of biological amines. Imide-type conjugates were generated from the dehydration and cyclization of amide-type conjugates. The structure of the conjugates was characterized by using the high-resolution mass spectrometry. We introduced the 14 N/ 15 N and 79 Br/ 81 Br isotope signatures to confirm the formation of conjugates using L-(ε) 15 N-lysine, L-lysine-15 N 2 , and bromine-tagged hydrazine, respectively. The structure of imide conjugate was also confirmed by NMR experiments. Furthermore, the amide and imide conjugates of cantharidin with amino acids or N-acetyl-lysine were detected in mouse liver and urine. Cantharidin was found to modify lysine residue proteins in mouse liver. Pan-P450 inhibitor 1-aminobenzotriazole significantly increased the urine cantharidin-N-acetyl-lysine conjugates whereas decreased cantharidin metabolites. In summary, cantharidin This article has not been copyedited and formatted. The final version may differ from this version.

show abstract

“…An investigation of intestinal permeability and first-pass metabolism of acetaminophen, verapamil, and midazolam using single-pass intestinal perfusion showed that 1-ABT increased the intestinal availability of these three drugs to 0.8–0.85 in cyanomologous monkeys, confirming that they are extensively metabolized in the intestine [ 108 ]. A significant increase in the exposure of mice to midazolam was observed when the mice were pretreated with 1-ABT [ 109 ]. The use of 1-ABT also demonstrated that intestinal metabolism, at least in part by CYP2J2, diminished the bioavailability in rats of AZ’0908, a prostaglandin E synthase-1 inhibitor [ 110 ].…”

Section: Analogues Of 1-abtmentioning

confidence: 99%

1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology

Montellano

2018

Med chem

View full text Add to dashboard Cite

1-Aminobenzotriazole (1-ABT) is a pan-specific, mechanism-based inactivator of the xenobiotic metabolizing forms of cytochrome P450 in animals, plants, insects, and microorganisms. It has been widely used to investigate the biological roles of cytochrome P450 enzymes, their participation in the metabolism of both endobiotics and xenobiotics, and their contributions to the metabolism-dependent toxicity of drugs and chemicals. This review is a comprehensive evaluation of the chemistry, discovery, and use of 1-aminobenzotriazole in these contexts from its introduction in 1981 to the present.

show abstract

A comparison of the metabolism of midazolam in C57BL/6J and hepatic reductase null (HRN) mice

Cited by 8 publications

References 20 publications

Application of Osmotic Pumps for Sustained Release of 1-Aminobenzotriazole and Inhibition of Cytochrome P450 Enzymes in Mice: Model Comparison with the Hepatic P450 Reductase Null Mouse

Application of Osmotic Pumps for Sustained Release of 1-Aminobenzotriazole and Inhibition of Cytochrome P450 Enzymes in Mice: Model Comparison with the Hepatic P450 Reductase Null Mouse

Covalent Binding of Reactive Anhydride of Cantharidin to Biological Amines

1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology

Contact Info

Product

Resources

About