Identification of Phase-I Metabolites of the Kv1.3 Blocker PAP-1 (5-(4-Phenoxybutoxy)psoralen) in the Rat
Identifieur interne : 000769 ( Pmc/Corpus ); précédent : 000768; suivant : 000770Identification of Phase-I Metabolites of the Kv1.3 Blocker PAP-1 (5-(4-Phenoxybutoxy)psoralen) in the Rat
Auteurs : Bin Hao ; Zhong-Wei Chen ; Xiang-Jun Zhou ; Pavel I. Zimin ; George P. Miljanich ; Heike Wulff ; Yong-Xiang WangSource :
- Xenobiotica; the fate of foreign compounds in biological systems [ 0049-8254 ] ; 2010.
Abstract
PAP-1 (5-(4-phenoxybutoxy)psoralen), a potent small-molecule blocker of the voltage-gated potassium Kv1.3 channel, is currently in pre-clinical development for psoriasis. The present study was undertaken to identify the major phase-I metabolites of PAP-1 in rats. Following oral administration at 50 mg/kg, bile, plasma, urine and feces were collected, and separated by reversed-phase HPLC after sample preparation by solid-phase extraction. Five phase-I metabolites, i.e., 5-(oxybutyric-acid)psoralen (M1), 5-[4-(4-hydroxybutoxy)]psoralen (M2), 5-[4-(4-hydroxyphenoxy)]psoralen (M3), 5-[4-(3-hydroxyphenoxy)]psoralen (M4), 8-hydroxyl-5-(4-phenoxybutoxy)psoralen (M5), were isolated and identified by mass spectrometry and NMR spectroscopy. M3, M4 and M5 were hydroxylated products, while M1 and M2 were O-dealkylation products. Incubation of PAP-1 with rat liver microsomes rendered the same five major metabolites in a NADPH-dependent manner suggesting that cytochrome P450 (CYP) enzymes are involved in PAP-1 metabolism. Inhibitors of rat CYP1A1/2 (alpha-naphthoflavone) and CYP3A (ketoconazole) but not CYP2D6, CYP2E or CYP2C9 blocked the metabolism of PAP-1 in rat microsomes. Of the five metabolites M3, M4 and M5 were found to inhibit Kv1.3 currents with nanomolar IC50s, while M1 and M2 were inactive. Our results identified the Kv1.3-inactive M1 as the major phase-I metabolite, and suggest that hydroxylation and O-dealkylation are the major pathways of PAP-1 metabolism principally via CYP1A1/2 and CYP3A. We further conducted a 6-months repeat-dose toxicity study with PAP-1 at 50 mg/kg in both male and female rats and did not observe any changes in hematology, blood chemistry, body weight, histology of any major organ, or speeding up of metabolism suggesting induction of its metabolizing enzymes (presumably CYPs).
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DOI: 10.3109/00498254.2010.532886
PubMed: 21070145
PubMed Central: 3644211
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PMC:3644211Le document en format XML
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<front><div type="abstract" xml:lang="en"><p id="P1">PAP-1 (5-(4-phenoxybutoxy)psoralen), a potent small-molecule blocker of the voltage-gated potassium Kv1.3 channel, is currently in pre-clinical development for psoriasis. The present study was undertaken to identify the major phase-I metabolites of PAP-1 in rats. Following oral administration at 50 mg/kg, bile, plasma, urine and feces were collected, and separated by reversed-phase HPLC after sample preparation by solid-phase extraction. Five phase-I metabolites, i.e., 5-(oxybutyric-acid)psoralen (M1), 5-[4-(4-hydroxybutoxy)]psoralen (M2), 5-[4-(4-hydroxyphenoxy)]psoralen (M3), 5-[4-(3-hydroxyphenoxy)]psoralen (M4), 8-hydroxyl-5-(4-phenoxybutoxy)psoralen (M5), were isolated and identified by mass spectrometry and NMR spectroscopy. M3, M4 and M5 were hydroxylated products, while M1 and M2 were O-dealkylation products. Incubation of PAP-1 with rat liver microsomes rendered the same five major metabolites in a NADPH-dependent manner suggesting that cytochrome P450 (CYP) enzymes are involved in PAP-1 metabolism. Inhibitors of rat CYP1A1/2 (alpha-naphthoflavone) and CYP3A (ketoconazole) but not CYP2D6, CYP2E or CYP2C9 blocked the metabolism of PAP-1 in rat microsomes. Of the five metabolites M3, M4 and M5 were found to inhibit Kv1.3 currents with nanomolar IC<sub>50</sub>
s, while M1 and M2 were inactive. Our results identified the Kv1.3-inactive M1 as the major phase-I metabolite, and suggest that hydroxylation and O-dealkylation are the major pathways of PAP-1 metabolism principally via CYP1A1/2 and CYP3A. We further conducted a 6-months repeat-dose toxicity study with PAP-1 at 50 mg/kg in both male and female rats and did not observe any changes in hematology, blood chemistry, body weight, histology of any major organ, or speeding up of metabolism suggesting induction of its metabolizing enzymes (presumably CYPs).</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">1306665</journal-id>
<journal-id journal-id-type="pubmed-jr-id">8102</journal-id>
<journal-id journal-id-type="nlm-ta">Xenobiotica</journal-id>
<journal-id journal-id-type="iso-abbrev">Xenobiotica</journal-id>
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<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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<title-group><article-title>Identification of Phase-I Metabolites of the Kv1.3 Blocker PAP-1 (5-(4-Phenoxybutoxy)psoralen) in the Rat</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Hao</surname>
<given-names>Bin</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
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<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Zhong-Wei</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhou</surname>
<given-names>Xiang-Jun</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zimin</surname>
<given-names>Pavel I.</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Miljanich</surname>
<given-names>George P.</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
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<contrib contrib-type="author"><name><surname>Wulff</surname>
<given-names>Heike</given-names>
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<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Yong-Xiang</given-names>
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<aff id="A1"><label>1</label>
King's Lab, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China</aff>
<aff id="A2"><label>2</label>
Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, GBSF Room 3502, Davis, CA 95616, USA</aff>
<aff id="A3"><label>3</label>
Airmid LLC, 600 Castle Hill Road, Redwood City, CA 94061, USA</aff>
<author-notes><corresp id="CR1"><bold>Corresponding authors</bold>
Yong-Xiang Wang King's Lab, School of Pharmacy, Shanghai Jiao Tong University Shanghai 200240, China <email>yxwang@sjtu.edu.cn</email>
Telephone/Fax: +86-21-3420-4763 Heike Wulff Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, GBSF Room 3502, Davis, CA 95616, USA <email>hwulff@ucdavis.edu</email>
Telephone: 530-754-6135</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>23</day>
<month>4</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>11</day>
<month>11</month>
<year>2010</year>
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<pub-date pub-type="ppub"><month>3</month>
<year>2011</year>
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<pub-date pub-type="pmc-release"><day>04</day>
<month>5</month>
<year>2013</year>
</pub-date>
<volume>41</volume>
<issue>3</issue>
<fpage>198</fpage>
<lpage>211</lpage>
<abstract><p id="P1">PAP-1 (5-(4-phenoxybutoxy)psoralen), a potent small-molecule blocker of the voltage-gated potassium Kv1.3 channel, is currently in pre-clinical development for psoriasis. The present study was undertaken to identify the major phase-I metabolites of PAP-1 in rats. Following oral administration at 50 mg/kg, bile, plasma, urine and feces were collected, and separated by reversed-phase HPLC after sample preparation by solid-phase extraction. Five phase-I metabolites, i.e., 5-(oxybutyric-acid)psoralen (M1), 5-[4-(4-hydroxybutoxy)]psoralen (M2), 5-[4-(4-hydroxyphenoxy)]psoralen (M3), 5-[4-(3-hydroxyphenoxy)]psoralen (M4), 8-hydroxyl-5-(4-phenoxybutoxy)psoralen (M5), were isolated and identified by mass spectrometry and NMR spectroscopy. M3, M4 and M5 were hydroxylated products, while M1 and M2 were O-dealkylation products. Incubation of PAP-1 with rat liver microsomes rendered the same five major metabolites in a NADPH-dependent manner suggesting that cytochrome P450 (CYP) enzymes are involved in PAP-1 metabolism. Inhibitors of rat CYP1A1/2 (alpha-naphthoflavone) and CYP3A (ketoconazole) but not CYP2D6, CYP2E or CYP2C9 blocked the metabolism of PAP-1 in rat microsomes. Of the five metabolites M3, M4 and M5 were found to inhibit Kv1.3 currents with nanomolar IC<sub>50</sub>
s, while M1 and M2 were inactive. Our results identified the Kv1.3-inactive M1 as the major phase-I metabolite, and suggest that hydroxylation and O-dealkylation are the major pathways of PAP-1 metabolism principally via CYP1A1/2 and CYP3A. We further conducted a 6-months repeat-dose toxicity study with PAP-1 at 50 mg/kg in both male and female rats and did not observe any changes in hematology, blood chemistry, body weight, histology of any major organ, or speeding up of metabolism suggesting induction of its metabolizing enzymes (presumably CYPs).</p>
</abstract>
<kwd-group><kwd>5-(4-phenoxybutoxy)psoralen (PAP-1)</kwd>
<kwd>Kv1.3 blocker</kwd>
<kwd>metabolism</kwd>
</kwd-group>
<funding-group><award-group><funding-source country="United States">National Institute of General Medical Sciences : NIGMS</funding-source>
<award-id>R01 GM076063 || GM</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
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