In Vivo Use of the CYP Inhibitor 1‐Aminobenzotriazole to Increase Long‐term Exposure in Mice

In this study, we demonstrated a suitable dosing vehicle of ABT for continuous administration and increased exposure of antipyrine, which is a nonspecific probe of CYP, using ABT for a long period in mice. The dosing vehicle of ABT was the 0.5% (w/v) hydroxypropyl methylcellulose and 0.5% (v/v) Tween 80 in N,N‐Dimethylacetamide/20% hydroxypropyl‐β‐cyclodextrin aqueous solution (2:8, v/v) based on the duration of apparent solubility. After implantation of an ALZET osmotic pump with ABT, the plasma concentrations of ABT were maintained at more than 4.1 µg/mL over 336 h. Compared to the vehicle group, CLtot of antipyrine with ABT decreased to approximately one‐fourth, and BA of antipyrine with ABT increased up to 3‐fold. In addition, the enhancement of exposure of antipyrine by ABT was maintained over the 336 h. The body weight, food consumption and hematological parameters of mice did not change with ABT administration for 16 days. These findings demonstrated that our pretreatment of ABT can increase long‐term exposure using continuous administration with the ALZET osmotic pump in mice with no overt toxicity. We concluded that in vivo use of ABT can be applied to pharmacological studies for proof‐of‐concept, thus contributing to the selection of drug candidates at an early drug discovery stage.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Short Communication Source Type: research