AI Article Synopsis
- Cytochrome P450 3A (CYP3A) activity is often measured by monitoring triazolam (TRZ) levels in CYP3A-humanised mice, but the relationship between TRZ concentrations and hepatic CYP3A activity hasn’t been clearly established.
- A study found that while TRZ and its metabolite α-hydroxy TRZ had similar plasma concentration profiles in both wild-type and Cyp3a-knockout mice, the area under the curve (AUC) for another metabolite, 4-OH TRZ, was significantly lower in the Cyp3a-KO mice.
- The findings suggest that monitoring plasma levels of 4-OH TRZ could serve as a
Article Abstract
1. To investigate cytochrome P450 3A (CYP3A)-mediated metabolism , plasma concentrations of triazolam (TRZ) are often monitored as a CYP3A marker in CYP3A-humanised mice. However, it has not been determined whether plasma concentrations of TRZ after intravenous administration can reflect hepatic CYP3A activity in CYP3A-humanised mice. 2. Firstly, we investigated the pharmacokinetics of TRZ in wild-type and Cyp3a-knockout (Cyp3a-KO) mice. Plasma concentration profiles of TRZ and α-hydroxy (OH) TRZ were very similar in wild-type and Cyp3a-KO mice. On the other hand, AUC of 4-OH TRZ in Cyp3a-KO mice was significantly lower than that in wild-type mice. Pregnenolone 16α-carbonitrile (PCN) decreased the areas under the plasma concentration-time curves (AUCs) of TRZ and α-OH TRZ in both groups. There was no significant effect of PCN on AUC of 4-OH TRZ in Cyp3a-KO mice. 3. Next, we verified that AUC of 4-OH TRZ in CYP3A-humanised mice was higher than that in Cyp3a-KO mice, although the difference was not significant. 4. In conclusion, plasma concentrations of 4-OH TRZ, but not those of TRZ and α-OH TRZ, might reflect hepatic CYP3A activity in mice . These results provide important insights for studies using a CYP3A-humanised model.
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Article Synopsis
- Cytochrome P450 3A (CYP3A) activity is often measured by monitoring triazolam (TRZ) levels in CYP3A-humanised mice, but the relationship between TRZ concentrations and hepatic CYP3A activity hasn’t been clearly established.
- A study found that while TRZ and its metabolite α-hydroxy TRZ had similar plasma concentration profiles in both wild-type and Cyp3a-knockout mice, the area under the curve (AUC) for another metabolite, 4-OH TRZ, was significantly lower in the Cyp3a-KO mice.
- The findings suggest that monitoring plasma levels of 4-OH TRZ could serve as a
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