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Determination of the Tissue Distribution and Excretion by Accelerator Mass Spectrometry of the Nonadecapeptide 14C-Moli1901 in Beagle dogs after Intratracheal Instillation

Administration of {sup 14}C-Moli1901 (duramycin, 2622U90), a 19 amino acid polycyclic peptide by intratracheal instillation (approximately 100 {micro}g) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. In this...

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Published in:	Chemico-biological interactions 2004-07, Vol.155 (1-2)
Main Authors:	Rickert, D E, Dingley, K H, Ubick, E, Dix, K J, Molina, L
Format:	Article
Language:	English
Subjects:	ACCELERATORS AMINO ACIDS BASIC BIOLOGICAL SCIENCES BEAGLES BILE BLOOD BRAIN EXCRETION FECES FIBROSIS INHALATION LIVER LUNGS MASS SPECTROSCOPY PARTICLE ACCELERATORS PATIENTS PEPTIDES PLASMA RETENTION SPLEEN TISSUE DISTRIBUTION URINE
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creator	Rickert, D E Dingley, K H Ubick, E Dix, K J Molina, L
description	Administration of {sup 14}C-Moli1901 (duramycin, 2622U90), a 19 amino acid polycyclic peptide by intratracheal instillation (approximately 100 {micro}g) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. In this study, we used accelerator mass spectrometry (AMS) to quantify Moli901 following administration of only 0.045 {micro}Ci of {sup 14}C-Moli901 per dog. Limits of quantitation of AMS were 0.03 (urine) to 0.3 (feces) ng equiv. Moli1901/g. Whole blood and plasma concentrations of {sup 14}C were
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During the first 3 days after the dose, plasma accounted for the majority of {sup 14}C in whole blood, but after that time, plasma accounted for only 25-30% of the {sup 14}C in whole blood. Tissue (left and right caudal lung lobe, liver, kidney, spleen, brain) and bile concentrations were low, always less than 0.25% the concentrations found in the left cranial lung lobe. Approximately 13% of the dose was eliminated in urine and feces in 28 days, with fecal elimination accounting for about 10% of the dose. The data presented here are consistent with that obtained in other species. Moli1901 is slowly absorbed and excreted from the lung, and it does not accumulate in other tissues. Moli1901 is currently in the clinic and has proven to be safe in single dose studies in human volunteers and cystic fibrosis patients by the inhalation route. No information on the disposition of the compound in humans is available. This study in dogs demonstrates the feasibility of obtaining that information using {sup 14}C-Moli1901 and AMS.</description><identifier>ISSN: 0009-2797</identifier><identifier>EISSN: 1872-7786</identifier><language>eng</language><publisher>United States</publisher><subject>ACCELERATORS ; AMINO ACIDS ; BASIC BIOLOGICAL SCIENCES ; BEAGLES ; BILE ; BLOOD ; BRAIN ; EXCRETION ; FECES ; FIBROSIS ; INHALATION ; LIVER ; LUNGS ; MASS SPECTROSCOPY ; PARTICLE ACCELERATORS ; PATIENTS ; PEPTIDES ; PLASMA ; RETENTION ; SPLEEN ; TISSUE DISTRIBUTION ; URINE</subject><ispartof>Chemico-biological interactions, 2004-07, Vol.155 (1-2)</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885</link.rule.ids><backlink>$$Uhttps://www.osti.gov/servlets/purl/875367$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Rickert, D E</creatorcontrib><creatorcontrib>Dingley, K H</creatorcontrib><creatorcontrib>Ubick, E</creatorcontrib><creatorcontrib>Dix, K J</creatorcontrib><creatorcontrib>Molina, L</creatorcontrib><creatorcontrib>Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)</creatorcontrib><title>Determination of the Tissue Distribution and Excretion by Accelerator Mass Spectrometry of the Nonadecapeptide 14C-Moli1901 in Beagle dogs after Intratracheal Instillation</title><title>Chemico-biological interactions</title><description>Administration of {sup 14}C-Moli1901 (duramycin, 2622U90), a 19 amino acid polycyclic peptide by intratracheal instillation (approximately 100 {micro}g) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. In this study, we used accelerator mass spectrometry (AMS) to quantify Moli901 following administration of only 0.045 {micro}Ci of {sup 14}C-Moli901 per dog. Limits of quantitation of AMS were 0.03 (urine) to 0.3 (feces) ng equiv. Moli1901/g. Whole blood and plasma concentrations of {sup 14}C were <5ng/ml at all times after the dose. Concentrations of {sup 14}C in whole blood and plasma declined over the first day after the dose and rose thereafter, with the rise in plasma concentrations lagging behind those in whole blood. During the first 3 days after the dose, plasma accounted for the majority of {sup 14}C in whole blood, but after that time, plasma accounted for only 25-30% of the {sup 14}C in whole blood. Tissue (left and right caudal lung lobe, liver, kidney, spleen, brain) and bile concentrations were low, always less than 0.25% the concentrations found in the left cranial lung lobe. Approximately 13% of the dose was eliminated in urine and feces in 28 days, with fecal elimination accounting for about 10% of the dose. The data presented here are consistent with that obtained in other species. Moli1901 is slowly absorbed and excreted from the lung, and it does not accumulate in other tissues. Moli1901 is currently in the clinic and has proven to be safe in single dose studies in human volunteers and cystic fibrosis patients by the inhalation route. No information on the disposition of the compound in humans is available. This study in dogs demonstrates the feasibility of obtaining that information using {sup 14}C-Moli1901 and AMS.</description><subject>ACCELERATORS</subject><subject>AMINO ACIDS</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>BEAGLES</subject><subject>BILE</subject><subject>BLOOD</subject><subject>BRAIN</subject><subject>EXCRETION</subject><subject>FECES</subject><subject>FIBROSIS</subject><subject>INHALATION</subject><subject>LIVER</subject><subject>LUNGS</subject><subject>MASS SPECTROSCOPY</subject><subject>PARTICLE ACCELERATORS</subject><subject>PATIENTS</subject><subject>PEPTIDES</subject><subject>PLASMA</subject><subject>RETENTION</subject><subject>SPLEEN</subject><subject>TISSUE DISTRIBUTION</subject><subject>URINE</subject><issn>0009-2797</issn><issn>1872-7786</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNqNjk1OwzAQhS0EEuHnDsMBIjlpqZMltEWwKBu6r6bOpDFy7cgzleiZuCRWBHtWT5_e09N3oYqqMXVpTLO4VIXWui1r05prdcP8mVHXc12o7xUJpaMLKC4GiD3IQLB1zCeClWNJbn-aKgwdrL9soon2Z3iyljwllJhgg8zwMZKVFI8k6fz39B4DdmRxpFFcR1DNl-Umele1ugIX4Jnw4Am6eGDAPqvAW5D8mdAOhD4Ti_N-srtTVz16pvvfvFUPL-vt8rWMebNj64TsYGMIWWPXmMfZwsz-s_kB-cRg_A</recordid><startdate>20040702</startdate><enddate>20040702</enddate><creator>Rickert, D E</creator><creator>Dingley, K H</creator><creator>Ubick, E</creator><creator>Dix, K J</creator><creator>Molina, L</creator><scope>OIOZB</scope><scope>OTOTI</scope></search><sort><creationdate>20040702</creationdate><title>Determination of the Tissue Distribution and Excretion by Accelerator Mass Spectrometry of the Nonadecapeptide 14C-Moli1901 in Beagle dogs after Intratracheal Instillation</title><author>Rickert, D E ; Dingley, K H ; Ubick, E ; Dix, K J ; Molina, L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-osti_scitechconnect_8753673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>ACCELERATORS</topic><topic>AMINO ACIDS</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>BEAGLES</topic><topic>BILE</topic><topic>BLOOD</topic><topic>BRAIN</topic><topic>EXCRETION</topic><topic>FECES</topic><topic>FIBROSIS</topic><topic>INHALATION</topic><topic>LIVER</topic><topic>LUNGS</topic><topic>MASS SPECTROSCOPY</topic><topic>PARTICLE ACCELERATORS</topic><topic>PATIENTS</topic><topic>PEPTIDES</topic><topic>PLASMA</topic><topic>RETENTION</topic><topic>SPLEEN</topic><topic>TISSUE DISTRIBUTION</topic><topic>URINE</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rickert, D E</creatorcontrib><creatorcontrib>Dingley, K H</creatorcontrib><creatorcontrib>Ubick, E</creatorcontrib><creatorcontrib>Dix, K J</creatorcontrib><creatorcontrib>Molina, L</creatorcontrib><creatorcontrib>Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)</creatorcontrib><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><jtitle>Chemico-biological interactions</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rickert, D E</au><au>Dingley, K H</au><au>Ubick, E</au><au>Dix, K J</au><au>Molina, L</au><aucorp>Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Determination of the Tissue Distribution and Excretion by Accelerator Mass Spectrometry of the Nonadecapeptide 14C-Moli1901 in Beagle dogs after Intratracheal Instillation</atitle><jtitle>Chemico-biological interactions</jtitle><date>2004-07-02</date><risdate>2004</risdate><volume>155</volume><issue>1-2</issue><issn>0009-2797</issn><eissn>1872-7786</eissn><abstract>Administration of {sup 14}C-Moli1901 (duramycin, 2622U90), a 19 amino acid polycyclic peptide by intratracheal instillation (approximately 100 {micro}g) into the left cranial lobe of the lung of beagle dogs resulted in retention of 64% of the dose in the left cranial lobe for up to 28 days. In this study, we used accelerator mass spectrometry (AMS) to quantify Moli901 following administration of only 0.045 {micro}Ci of {sup 14}C-Moli901 per dog. Limits of quantitation of AMS were 0.03 (urine) to 0.3 (feces) ng equiv. Moli1901/g. Whole blood and plasma concentrations of {sup 14}C were <5ng/ml at all times after the dose. Concentrations of {sup 14}C in whole blood and plasma declined over the first day after the dose and rose thereafter, with the rise in plasma concentrations lagging behind those in whole blood. During the first 3 days after the dose, plasma accounted for the majority of {sup 14}C in whole blood, but after that time, plasma accounted for only 25-30% of the {sup 14}C in whole blood. Tissue (left and right caudal lung lobe, liver, kidney, spleen, brain) and bile concentrations were low, always less than 0.25% the concentrations found in the left cranial lung lobe. Approximately 13% of the dose was eliminated in urine and feces in 28 days, with fecal elimination accounting for about 10% of the dose. The data presented here are consistent with that obtained in other species. Moli1901 is slowly absorbed and excreted from the lung, and it does not accumulate in other tissues. Moli1901 is currently in the clinic and has proven to be safe in single dose studies in human volunteers and cystic fibrosis patients by the inhalation route. No information on the disposition of the compound in humans is available. This study in dogs demonstrates the feasibility of obtaining that information using {sup 14}C-Moli1901 and AMS.</abstract><cop>United States</cop><oa>free_for_read</oa></addata></record>
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subjects	ACCELERATORS AMINO ACIDS BASIC BIOLOGICAL SCIENCES BEAGLES BILE BLOOD BRAIN EXCRETION FECES FIBROSIS INHALATION LIVER LUNGS MASS SPECTROSCOPY PARTICLE ACCELERATORS PATIENTS PEPTIDES PLASMA RETENTION SPLEEN TISSUE DISTRIBUTION URINE
title	Determination of the Tissue Distribution and Excretion by Accelerator Mass Spectrometry of the Nonadecapeptide 14C-Moli1901 in Beagle dogs after Intratracheal Instillation
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