Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug
Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte function-associated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and...
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| Veröffentlicht in: | Xenobiotica 2008-03, Vol.38 (3), p.340-352 |
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| creator | Khojasteh, S. C. Leipold, D. D. Lai, F. La, H. Baumgardner, M. J. Desino, K. E. Gudmundsson, O. S. Bloedow, D. C. Bodary, S. C. Reynolds, M. E. Gadek, T. R. Kenkare-Mitra, S. |
| description | Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte function-associated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min−1 kg−1, respectively.
In mass balance studies using [14C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose.
In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9.
In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9.
In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988. |
| doi_str_mv | 10.1080/00498250701813248 |
| format | Article |
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In mass balance studies using [14C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose.
In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9.
In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9.
In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.</description><identifier>ISSN: 0049-8254</identifier><identifier>EISSN: 1366-5928</identifier><identifier>DOI: 10.1080/00498250701813248</identifier><identifier>PMID: 18274961</identifier><language>eng</language><publisher>England: Informa UK Ltd</publisher><subject>Absorption - drug effects ; Acrylamides - chemistry ; Acrylamides - metabolism ; Acrylamides - pharmacokinetics ; Acrylamides - pharmacology ; Animals ; beta-Alanine - analogs & derivatives ; beta-Alanine - chemistry ; beta-Alanine - metabolism ; beta-Alanine - pharmacokinetics ; beta-Alanine - pharmacology ; Cell Adhesion Molecules - chemistry ; Cell Adhesion Molecules - metabolism ; Cell Adhesion Molecules - pharmacokinetics ; Cell Adhesion Molecules - pharmacology ; distribution ; Dogs ; Drug Evaluation, Preclinical ; Drug Stability ; esterase ; Haplorhini ; Humans ; Injections, Intravenous ; intercellular adhesion molecule (ICAM) ; Liver - drug effects ; Liver - metabolism ; Lymphocyte function-associated antigen-1 (LFA-1) ; Lymphocyte Function-Associated Antigen-1 - metabolism ; metabolism and excretion (ADME); metabolism ; Mice ; pharmacokinetics ; prodrug; absorption ; Prodrugs - chemistry ; Prodrugs - metabolism ; Prodrugs - pharmacokinetics ; Prodrugs - pharmacology ; Rats ; Tissue Distribution - drug effects</subject><ispartof>Xenobiotica, 2008-03, Vol.38 (3), p.340-352</ispartof><rights>2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted 2008</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-6435186a6558c8f600d0869b483241008db82d1261e3d330948c492726f53bf63</citedby><cites>FETCH-LOGICAL-c404t-6435186a6558c8f600d0869b483241008db82d1261e3d330948c492726f53bf63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.1080/00498250701813248$$EPDF$$P50$$Ginformahealthcare$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.1080/00498250701813248$$EHTML$$P50$$Ginformahealthcare$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,59626,59732,60415,60521,61200,61235,61381,61416</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18274961$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Khojasteh, S. C.</creatorcontrib><creatorcontrib>Leipold, D. D.</creatorcontrib><creatorcontrib>Lai, F.</creatorcontrib><creatorcontrib>La, H.</creatorcontrib><creatorcontrib>Baumgardner, M. J.</creatorcontrib><creatorcontrib>Desino, K. E.</creatorcontrib><creatorcontrib>Gudmundsson, O. S.</creatorcontrib><creatorcontrib>Bloedow, D. C.</creatorcontrib><creatorcontrib>Bodary, S. C.</creatorcontrib><creatorcontrib>Reynolds, M. E.</creatorcontrib><creatorcontrib>Gadek, T. R.</creatorcontrib><creatorcontrib>Kenkare-Mitra, S.</creatorcontrib><title>Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug</title><title>Xenobiotica</title><addtitle>Xenobiotica</addtitle><description>Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte function-associated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min−1 kg−1, respectively.
In mass balance studies using [14C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose.
In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9.
In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9.
In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.</description><subject>Absorption - drug effects</subject><subject>Acrylamides - chemistry</subject><subject>Acrylamides - metabolism</subject><subject>Acrylamides - pharmacokinetics</subject><subject>Acrylamides - pharmacology</subject><subject>Animals</subject><subject>beta-Alanine - analogs & derivatives</subject><subject>beta-Alanine - chemistry</subject><subject>beta-Alanine - metabolism</subject><subject>beta-Alanine - pharmacokinetics</subject><subject>beta-Alanine - pharmacology</subject><subject>Cell Adhesion Molecules - chemistry</subject><subject>Cell Adhesion Molecules - metabolism</subject><subject>Cell Adhesion Molecules - pharmacokinetics</subject><subject>Cell Adhesion Molecules - pharmacology</subject><subject>distribution</subject><subject>Dogs</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Stability</subject><subject>esterase</subject><subject>Haplorhini</subject><subject>Humans</subject><subject>Injections, Intravenous</subject><subject>intercellular adhesion molecule (ICAM)</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Lymphocyte function-associated antigen-1 (LFA-1)</subject><subject>Lymphocyte Function-Associated Antigen-1 - metabolism</subject><subject>metabolism and excretion (ADME); metabolism</subject><subject>Mice</subject><subject>pharmacokinetics</subject><subject>prodrug; absorption</subject><subject>Prodrugs - chemistry</subject><subject>Prodrugs - metabolism</subject><subject>Prodrugs - pharmacokinetics</subject><subject>Prodrugs - pharmacology</subject><subject>Rats</subject><subject>Tissue Distribution - drug effects</subject><issn>0049-8254</issn><issn>1366-5928</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-KFDEQxoMo7rj6AF4kJ1GYdit_OpNGL8O6q8IsetBzSCfpnSzpzpik0fUdfGczOwMiwp5CVf2-r8JXCD0n8IaAhDMA3knawgqIJIxy-QAtCBOiaTsqH6LFft5UgJ-gJznfAIAglD5GJ0TSFe8EWaDfX5IzwU_e6IB1n2PaFR-nJbY-l-T7-VCNrug-Bp9HrCeL3U-T3H6CX63fX128xmarkzbFJf9L3_XjgD-dr69IJ-WySvDmct2Qs32rVkVfx6n6L-_MfMl4l6JN8_VT9GjQIbtnx_cUfbu8-Hr-sdl8_lC1m8Zw4KURnLVECi3aVho5CAALUnQ9lzUEAiBtL6klVBDHLGPQcWl4R1dUDC3rB8FO0cuDb937fXa5qNFn40LQk4tzViugHXAqK0gOoEkx5-QGtUt-1OlWEVD7G6j_blA1L47mcz86-1dxDL0C7w6An4aYRv0jpmBV0bchpiHpyfis2H3-b_-Rb50OZWt0cuomzmmqwd3zuz_Y9KQ6</recordid><startdate>200803</startdate><enddate>200803</enddate><creator>Khojasteh, S. C.</creator><creator>Leipold, D. D.</creator><creator>Lai, F.</creator><creator>La, H.</creator><creator>Baumgardner, M. J.</creator><creator>Desino, K. E.</creator><creator>Gudmundsson, O. S.</creator><creator>Bloedow, D. C.</creator><creator>Bodary, S. C.</creator><creator>Reynolds, M. E.</creator><creator>Gadek, T. R.</creator><creator>Kenkare-Mitra, S.</creator><general>Informa UK Ltd</general><general>Taylor & Francis</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200803</creationdate><title>Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug</title><author>Khojasteh, S. C. ; Leipold, D. D. ; Lai, F. ; La, H. ; Baumgardner, M. J. ; Desino, K. E. ; Gudmundsson, O. S. ; Bloedow, D. C. ; Bodary, S. C. ; Reynolds, M. E. ; Gadek, T. R. ; Kenkare-Mitra, S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-6435186a6558c8f600d0869b483241008db82d1261e3d330948c492726f53bf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Absorption - drug effects</topic><topic>Acrylamides - chemistry</topic><topic>Acrylamides - metabolism</topic><topic>Acrylamides - pharmacokinetics</topic><topic>Acrylamides - pharmacology</topic><topic>Animals</topic><topic>beta-Alanine - analogs & derivatives</topic><topic>beta-Alanine - chemistry</topic><topic>beta-Alanine - metabolism</topic><topic>beta-Alanine - pharmacokinetics</topic><topic>beta-Alanine - pharmacology</topic><topic>Cell Adhesion Molecules - chemistry</topic><topic>Cell Adhesion Molecules - metabolism</topic><topic>Cell Adhesion Molecules - pharmacokinetics</topic><topic>Cell Adhesion Molecules - pharmacology</topic><topic>distribution</topic><topic>Dogs</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Stability</topic><topic>esterase</topic><topic>Haplorhini</topic><topic>Humans</topic><topic>Injections, Intravenous</topic><topic>intercellular adhesion molecule (ICAM)</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Lymphocyte function-associated antigen-1 (LFA-1)</topic><topic>Lymphocyte Function-Associated Antigen-1 - metabolism</topic><topic>metabolism and excretion (ADME); metabolism</topic><topic>Mice</topic><topic>pharmacokinetics</topic><topic>prodrug; absorption</topic><topic>Prodrugs - chemistry</topic><topic>Prodrugs - metabolism</topic><topic>Prodrugs - pharmacokinetics</topic><topic>Prodrugs - pharmacology</topic><topic>Rats</topic><topic>Tissue Distribution - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Khojasteh, S. C.</creatorcontrib><creatorcontrib>Leipold, D. D.</creatorcontrib><creatorcontrib>Lai, F.</creatorcontrib><creatorcontrib>La, H.</creatorcontrib><creatorcontrib>Baumgardner, M. J.</creatorcontrib><creatorcontrib>Desino, K. E.</creatorcontrib><creatorcontrib>Gudmundsson, O. S.</creatorcontrib><creatorcontrib>Bloedow, D. C.</creatorcontrib><creatorcontrib>Bodary, S. C.</creatorcontrib><creatorcontrib>Reynolds, M. E.</creatorcontrib><creatorcontrib>Gadek, T. R.</creatorcontrib><creatorcontrib>Kenkare-Mitra, S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Xenobiotica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Khojasteh, S. C.</au><au>Leipold, D. D.</au><au>Lai, F.</au><au>La, H.</au><au>Baumgardner, M. J.</au><au>Desino, K. E.</au><au>Gudmundsson, O. S.</au><au>Bloedow, D. C.</au><au>Bodary, S. C.</au><au>Reynolds, M. E.</au><au>Gadek, T. R.</au><au>Kenkare-Mitra, S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug</atitle><jtitle>Xenobiotica</jtitle><addtitle>Xenobiotica</addtitle><date>2008-03</date><risdate>2008</risdate><volume>38</volume><issue>3</issue><spage>340</spage><epage>352</epage><pages>340-352</pages><issn>0049-8254</issn><eissn>1366-5928</eissn><abstract>Intercellular adhesion molecule (ICAM)-1988 is a small molecule lymphocyte function-associated antigen-1 (LFA-1) antagonist being considered for its anti-inflammatory properties. Following intravenous administration of ICAM1988, clearances in mice, rats, dogs, and monkeys were 17.8, 3.31, 15.4, and 6.85 ml min−1 kg−1, respectively.
In mass balance studies using [14C]-ICAM1988 in rats dosed intravenously, unchanged ICAM1988 contributed to 25.1% of the dose.
In rats, the systemic bioavailability of ICAM1988 was improved to 0.28 when the drug was administered orally as its isobutyl ester, ICAM2660. In rats, this was consistent with the complete in vitro conversion of ICAM2660 to ICAM1988 in plasma, and liver and intestinal S9.
In dogs and monkeys, ICAM2660 did not improve the bioavailability of ICAM1988. This is consistent with limited in vitro conversion of ICAM2660 to ICAM1988 in plasma and liver S9.
In human in vitro studies, ICAM2660 conversion to ICAM1988 in liver was similar to rats while no conversion in plasma and intestinal S9 fractions were observed. Based on the in vitro metabolism similarities of human and rat, it would be anticipated that in human oral administration of ICAM2660 would improve the systemic exposure of ICAM1988.</abstract><cop>England</cop><pub>Informa UK Ltd</pub><pmid>18274961</pmid><doi>10.1080/00498250701813248</doi><tpages>13</tpages></addata></record> |
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| ispartof | Xenobiotica, 2008-03, Vol.38 (3), p.340-352 |
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| subjects | Absorption - drug effects Acrylamides - chemistry Acrylamides - metabolism Acrylamides - pharmacokinetics Acrylamides - pharmacology Animals beta-Alanine - analogs & derivatives beta-Alanine - chemistry beta-Alanine - metabolism beta-Alanine - pharmacokinetics beta-Alanine - pharmacology Cell Adhesion Molecules - chemistry Cell Adhesion Molecules - metabolism Cell Adhesion Molecules - pharmacokinetics Cell Adhesion Molecules - pharmacology distribution Dogs Drug Evaluation, Preclinical Drug Stability esterase Haplorhini Humans Injections, Intravenous intercellular adhesion molecule (ICAM) Liver - drug effects Liver - metabolism Lymphocyte function-associated antigen-1 (LFA-1) Lymphocyte Function-Associated Antigen-1 - metabolism metabolism and excretion (ADME) metabolism Mice pharmacokinetics prodrug absorption Prodrugs - chemistry Prodrugs - metabolism Prodrugs - pharmacokinetics Prodrugs - pharmacology Rats Tissue Distribution - drug effects |
| title | Preclinical absorption, distribution, metabolism and excretion (ADME) characterization of ICAM1988, an LFA-1/ICAM antagonist, and its prodrug |
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