ArticleNuclear medicine and biology2010
Effects of ketoconazole on the biodistribution and metabolism of [11C]loperamide and [11C]N-desmethyl-loperamide in wild-type and P-gp knockout mice.
Article in Nuclear medicine and biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
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- Measurement of Hepatic CYP3A4 and 2D6 Activity Using Radioiodine-LabeledInternational journal of molecular sciences · 2022Article
- The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine.British journal of pharmacology · 2022Article
- Assessing Drug Interaction and Pharmacokinetics of Loxoprofen in Mice Treated with CYP3A Modulators.Pharmaceutics · 2019Article
- Breaking Bad: the Structure and Function of the Blood-Brain Barrier in Epilepsy.The AAPS journal · 2017Review
- Sunitinib tissue distribution changes after coadministration with ketoconazole in mice.European journal of drug metabolism and pharmacokinetics · 2016Article
- Factors Governing P-Glycoprotein-Mediated Drug-Drug Interactions at the Blood-Brain Barrier Measured with Positron Emission Tomography.Molecular pharmaceutics · 2015Article
- The dilemma of foraging herbivores: dealing with food and fear.Oecologia · 2014Article
- PET and SPECT radiotracers to assess function and expression of ABC transporters in vivo.Current drug metabolism · 2011Review
- Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein.Bioorganic & medicinal chemistry · 2011Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
introduction[(11)C]Loperamide and [(11)C]N-desmethyl-loperamide ([(11)C]dLop) have been proposed as radiotracers for imaging brain P-glycoprotein (P-gp) function. A major route of [(11)C]loperamide metabolism is N-demethylation to [(11)C]dLop. We aimed to test whether inhibition of CYP3A4 with ketoconazole might reduce the metabolism of [(11)C]loperamide and [(11)C]dLop in mice, and thereby improve the quality of these radiotracers.
methodsStudies 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 [(11)C]loperamide or [(11)C]dLop. Whole brain and plasma samples were measured for radioactivity and analyzed with radio-high-performance liquid chromatography.
resultsKetoconazole increased the plasma concentrations of [(11)C]loperamide and its main radiometabolite, [(11)C]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 [(11)C]loperamide and the radiometabolite [(11)C]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 [(11)C]dLop and its radiometabolites in either wild-type or knockout mice, except to increase the low plasma [(11)C]dLop concentration. The least polar radiometabolite of [(11)C]dLop was identified with LC-MS(n) as the N-hydroxymethyl analog of [(11)C]dLop and this also behaved as a P-gp substrate.
conclusionIn this study, ketoconazole (50 mg/kg, ip) proved partially effective for inhibiting the N-demethylation of [(11)C]loperamide in mouse in vivo but had relatively smaller or no effect on [(11)C]dLop.
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