Abstract
The human cytochrome P450 (P450) system is implicated in many drug interactions. Lisdexamfetamine dimesylate (NRP104), the proposed generic name for a new agent under investigation for treatment of attention deficit hyperactivity disorder, was recently analyzed for inhibitory drug-drug interactions with seven major P450 isoforms using pooled human liver microsomes. Probe substrates were used near the Km concentration values reported in the literature for CYP1A2 (phenacetin), CYP2A6 (coumarin), CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2C19 ([S]-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4 (midazolam and testosterone), and lisdexamfetamine was evaluated at concentrations ranging from 0.01 to 100 μM for its ability to inhibit the activity of these seven P450 isoforms. NADPH was added to one set of samples to initiate metabolic reactions, which were then terminated by adding organic solvent, vortexing the samples, and placing them on ice. The relevant substrates were then introduced to both sets of samples so that the percentage of remaining activity could be measured and compared. In addition, these samples were compared with other samples with the same concentrations of lisdexamfetamine but without preincubation. None of the seven P450 isoforms showed any concentration-dependent inhibition. Comparison of results from microsomes preincubated with and without NADPH showed no mechanism-based inhibition. Neither concentration-dependent nor mechanism-based inhibition caused by time-dependent inactivation of human P450 isoforms was shown for lisdexamfetamine during in vitro testing. The evidence suggests that lisdexamfetamine has a low potential for drug-drug interactions or initiation of drug-drug interactions.
Footnotes
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Supported by New River Pharmaceuticals, Inc. and Shire Development, Inc. Chemical nomenclature of investigational compound: (2S,2;S)-2,6-diamino-N-(1-phenylpropan-2-yl) hexamide di-methanesulfonate; molecular weight: 455.59; generic name: lisdexamfetamine dimesylate; CAS numbers: 608137-32-2 (free base); 608137-33-3 (mesylate).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.011973.
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ABBREVIATIONS: ADHD, attention deficit hyperactivity disorder; P450, cytochrome P450; HPLC, high-performance liquid chromatography; APAP, acetaminophen; 7OHCMN, 7-hydroxycoumarin; OHBP, hydroxybupropion; HTB, hydroxytolbutamide; 4HMPN, 4′-hydroxymephenytoin; DRR, dextrorphan; 1OHMDZ, 1′-hydroxymidazolam; 6βT, 6β-hydroxytestosterone; QC, quality control; LC/MS/MS, liquid chromatography/tandem mass spectrometry.
- Received July 13, 2006.
- Accepted October 6, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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