Effects of ketoconazole on the biodistribution and metabolism of [¹¹C]loperamide and [¹¹C]N-desmethyl-loperamide in wild-type and P-gp knockout mice

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• 作者：Nicholas Seneca ; Sami S. Zoghbi ; H. Umesha Shetty ; Edward Tuan ; Pavitra Kannan ; Andrew Taku ; Robert B. Innis ; Victor W. Pike
• 关键词：[¹¹C]Loperamide ; [¹¹C]dLop ; P-glycoprotein ; Ketoconazole ; Biodistribution ; Metabolism
• 刊名：Nuclear Medicine and Biology
• 出版年：2010
• 出版时间：April 2010
• 年：2010
• 卷：37
• 期：3
• 页码：335-345
• 全文大小：520 K

文摘

Introduction

[¹¹C]Loperamide and [¹¹C]N-desmethyl-loperamide ([¹¹C]dLop) have been proposed as radiotracers for imaging brain P-glycoprotein (P-gp) function. A major route of [¹¹C]loperamide metabolism is N-demethylation to [¹¹C]dLop. We aimed to test whether inhibition of CYP3A4 with ketoconazole might reduce the metabolism of [¹¹C]loperamide and [¹¹C]dLop in mice, and thereby improve the quality of these radiotracers.

Methods

Studies were performed in wild-type and P-gp knockout (mdr−1a/b −/−) mice. During each of seven study sessions, one pair of mice, comprising one wild-type and one knockout mouse, was pretreated with ketoconazole (50 mg/kg, ip), while another such pair was left untreated. Mice were sacrificed at 30 min after injection of [¹¹C]loperamide or [¹¹C]dLop. Whole brain and plasma samples were measured for radioactivity and analyzed with radio-high-performance liquid chromatography.

Results

Ketoconazole increased the plasma concentrations of [¹¹C]loperamide and its main radiometabolite, [¹¹C]dLop, by about twofold in both wild-type and knockout mice, whereas the most polar radiometabolite was decreased threefold. Furthermore, ketoconazole increased the brain concentrations of [¹¹C]loperamide and the radiometabolite [¹¹C]dLop by about twofold in knockout mice, and decreased the brain concentrations of the major and most polar radiometabolite in wild-type and knockout mice by 82 % and 49 % , respectively. In contrast, ketoconazole had no effect on plasma and brain distribution of administered [¹¹C]dLop and its radiometabolites in either wild-type or knockout mice, except to increase the low plasma [¹¹C]dLop concentration. The least polar radiometabolite of [¹¹C]dLop was identified with LC-MSⁿ as the N-hydroxymethyl analog of [¹¹C]dLop and this also behaved as a P-gp substrate.

Conclusion

In this study, ketoconazole (50 mg/kg, ip) proved partially effective for inhibiting the N-demethylation of [¹¹C]loperamide in mouse in vivo but had relatively smaller or no effect on [¹¹C]dLop.