Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01, Caused by Specific High Affinity Binding to alpha sub(1)-Acid Glycoprotein in Humans
The large species difference in the pharmacokinetics/pharmacodynamics of 7-hydroxystaurosporine (UCN-01) can be partially explained by the high affinity binding of UCN-01 to human alpha sub(1)-acid glycoprotein (AGP) (Fuse et al., Cancer Res., 58: 3248-3253, 1998). To confirm whether its binding to...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 1999-03, Vol.59 (5), p.1054-1060 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Fuse, E Tanii, H Takai, K Asanome, K Kurata, N Kobayashi, H Kuwabara, T Kobayashi, S Sugiyama, Y |
| description | The large species difference in the pharmacokinetics/pharmacodynamics of 7-hydroxystaurosporine (UCN-01) can be partially explained by the high affinity binding of UCN-01 to human alpha sub(1)-acid glycoprotein (AGP) (Fuse et al., Cancer Res., 58: 3248-3253, 1998). To confirm whether its binding to human AGP actually changes the in vivo pharmacokinetics, we have studied the alteration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing its dissociation from proteins using dextran-coated charcoal. The UCN-01 remaining 0.1 h after adding dextran-coated charcoal to human plasma or AGP was similar to 80%, although the values for other specimens, except monkey plasma ( similar to 20%), were |
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To confirm whether its binding to human AGP actually changes the in vivo pharmacokinetics, we have studied the alteration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing its dissociation from proteins using dextran-coated charcoal. The UCN-01 remaining 0.1 h after adding dextran-coated charcoal to human plasma or AGP was similar to 80%, although the values for other specimens, except monkey plasma ( similar to 20%), were <1%, indicating that the dissociation from human AGP was specifically slower than from other proteins; and (b) the pharmacokinetics of UCN-01 simultaneously administered with human AGP has been determined. The plasma concentrations after i.v. administration of UCN-01 with equimolar human AGP were much higher than those after administration of UCN-01 alone. The steady-state distribution volume and the systemic clearance were reduced to about 1/100 and 1/200, respectively. Human AGP thus reduced the distribution and elimination of UCN-01 substantially. On the other hand, dog AGP, which has a low binding affinity for UCN-01, did not change the pharmacokinetics of UCN-01 so much. Furthermore, human AGP markedly reduced the hepatic extraction ratio of UCN-01 from 0.510 to 0.0326. Also, human AGP (10 mu M) completely inhibited the initial uptake of UCN-01 was unchanged in the presence of human serum albumin (10 mu M). In conclusion, the high degree of binding of UCN-01 to human AGP causes a reduction in the distribution and clearance, resulting in high plasma concentrations in humans.</description><identifier>ISSN: 0008-5472</identifier><language>eng</language><ispartof>Cancer research (Chicago, Ill.), 1999-03, Vol.59 (5), p.1054-1060</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids></links><search><creatorcontrib>Fuse, E</creatorcontrib><creatorcontrib>Tanii, H</creatorcontrib><creatorcontrib>Takai, K</creatorcontrib><creatorcontrib>Asanome, K</creatorcontrib><creatorcontrib>Kurata, N</creatorcontrib><creatorcontrib>Kobayashi, H</creatorcontrib><creatorcontrib>Kuwabara, T</creatorcontrib><creatorcontrib>Kobayashi, S</creatorcontrib><creatorcontrib>Sugiyama, Y</creatorcontrib><title>Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01, Caused by Specific High Affinity Binding to alpha sub(1)-Acid Glycoprotein in Humans</title><title>Cancer research (Chicago, Ill.)</title><description>The large species difference in the pharmacokinetics/pharmacodynamics of 7-hydroxystaurosporine (UCN-01) can be partially explained by the high affinity binding of UCN-01 to human alpha sub(1)-acid glycoprotein (AGP) (Fuse et al., Cancer Res., 58: 3248-3253, 1998). To confirm whether its binding to human AGP actually changes the in vivo pharmacokinetics, we have studied the alteration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing its dissociation from proteins using dextran-coated charcoal. The UCN-01 remaining 0.1 h after adding dextran-coated charcoal to human plasma or AGP was similar to 80%, although the values for other specimens, except monkey plasma ( similar to 20%), were <1%, indicating that the dissociation from human AGP was specifically slower than from other proteins; and (b) the pharmacokinetics of UCN-01 simultaneously administered with human AGP has been determined. The plasma concentrations after i.v. administration of UCN-01 with equimolar human AGP were much higher than those after administration of UCN-01 alone. The steady-state distribution volume and the systemic clearance were reduced to about 1/100 and 1/200, respectively. Human AGP thus reduced the distribution and elimination of UCN-01 substantially. On the other hand, dog AGP, which has a low binding affinity for UCN-01, did not change the pharmacokinetics of UCN-01 so much. Furthermore, human AGP markedly reduced the hepatic extraction ratio of UCN-01 from 0.510 to 0.0326. Also, human AGP (10 mu M) completely inhibited the initial uptake of UCN-01 was unchanged in the presence of human serum albumin (10 mu M). In conclusion, the high degree of binding of UCN-01 to human AGP causes a reduction in the distribution and clearance, resulting in high plasma concentrations in humans.</description><issn>0008-5472</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNqNi81KxDAUhbNQcHR8h7sShSmkMy11W-tPV4Ogsx7upDft1TSpTSL0MXxjs_ABhAOH8_GdM7GSUt5nZVFtL8Sl9x9plrksV-KnNoFm6uB1wHlE5T7ZUmDlwWlA2LtvMlDbRNAqmuFxjv0GDs0-k_kGGow-fU8LvE2kWLOClvsBaq3ZcljggW3HtofgAM00IPh4us3vslpxBy9mUW6aXSC2kNLGEa1fi3ONxtP1X1-Jm-en96bNkvkVyYfjyF6RMWjJRX_Mq50sqmK7-7f4C8L0VpM</recordid><startdate>19990301</startdate><enddate>19990301</enddate><creator>Fuse, E</creator><creator>Tanii, H</creator><creator>Takai, K</creator><creator>Asanome, K</creator><creator>Kurata, N</creator><creator>Kobayashi, H</creator><creator>Kuwabara, T</creator><creator>Kobayashi, S</creator><creator>Sugiyama, Y</creator><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>19990301</creationdate><title>Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01, Caused by Specific High Affinity Binding to alpha sub(1)-Acid Glycoprotein in Humans</title><author>Fuse, E ; Tanii, H ; Takai, K ; Asanome, K ; Kurata, N ; Kobayashi, H ; Kuwabara, T ; Kobayashi, S ; Sugiyama, Y</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_miscellaneous_173047423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fuse, E</creatorcontrib><creatorcontrib>Tanii, H</creatorcontrib><creatorcontrib>Takai, K</creatorcontrib><creatorcontrib>Asanome, K</creatorcontrib><creatorcontrib>Kurata, N</creatorcontrib><creatorcontrib>Kobayashi, H</creatorcontrib><creatorcontrib>Kuwabara, T</creatorcontrib><creatorcontrib>Kobayashi, S</creatorcontrib><creatorcontrib>Sugiyama, Y</creatorcontrib><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fuse, E</au><au>Tanii, H</au><au>Takai, K</au><au>Asanome, K</au><au>Kurata, N</au><au>Kobayashi, H</au><au>Kuwabara, T</au><au>Kobayashi, S</au><au>Sugiyama, Y</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01, Caused by Specific High Affinity Binding to alpha sub(1)-Acid Glycoprotein in Humans</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><date>1999-03-01</date><risdate>1999</risdate><volume>59</volume><issue>5</issue><spage>1054</spage><epage>1060</epage><pages>1054-1060</pages><issn>0008-5472</issn><abstract>The large species difference in the pharmacokinetics/pharmacodynamics of 7-hydroxystaurosporine (UCN-01) can be partially explained by the high affinity binding of UCN-01 to human alpha sub(1)-acid glycoprotein (AGP) (Fuse et al., Cancer Res., 58: 3248-3253, 1998). To confirm whether its binding to human AGP actually changes the in vivo pharmacokinetics, we have studied the alteration in its pharmacokinetics after simultaneous administration of human AGP to rats: (a) the protein binding of UCN-01 was evaluated by chasing its dissociation from proteins using dextran-coated charcoal. The UCN-01 remaining 0.1 h after adding dextran-coated charcoal to human plasma or AGP was similar to 80%, although the values for other specimens, except monkey plasma ( similar to 20%), were <1%, indicating that the dissociation from human AGP was specifically slower than from other proteins; and (b) the pharmacokinetics of UCN-01 simultaneously administered with human AGP has been determined. The plasma concentrations after i.v. administration of UCN-01 with equimolar human AGP were much higher than those after administration of UCN-01 alone. The steady-state distribution volume and the systemic clearance were reduced to about 1/100 and 1/200, respectively. Human AGP thus reduced the distribution and elimination of UCN-01 substantially. On the other hand, dog AGP, which has a low binding affinity for UCN-01, did not change the pharmacokinetics of UCN-01 so much. Furthermore, human AGP markedly reduced the hepatic extraction ratio of UCN-01 from 0.510 to 0.0326. Also, human AGP (10 mu M) completely inhibited the initial uptake of UCN-01 was unchanged in the presence of human serum albumin (10 mu M). In conclusion, the high degree of binding of UCN-01 to human AGP causes a reduction in the distribution and clearance, resulting in high plasma concentrations in humans.</abstract></addata></record> |
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| title | Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01, Caused by Specific High Affinity Binding to alpha sub(1)-Acid Glycoprotein in Humans |
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