Investigation of the influence of modulation of P-glycoprotein by a multiple dosing regimen of tamoxifen on the pharmacokinetics and toxicodynamics of doxorubicin
The in vivo effect of modulators of P-glycoprotein (Pgp) on organ accumulation of substrates of Pgp has not been fully investigated. We investigated the influence of a Pgp modulator (tamoxifen, TAM) on the pharmacokinetics and toxicodynamics of a Pgp substrate (doxorubicin, DOX) in rats. TAM was adm...
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| description | The in vivo effect of modulators of P-glycoprotein (Pgp) on organ accumulation of substrates of Pgp has not been fully investigated. We investigated the influence of a Pgp modulator (tamoxifen, TAM) on the pharmacokinetics and toxicodynamics of a Pgp substrate (doxorubicin, DOX) in rats.
TAM was administered daily for 11 days before the administration of DOX in male Sprague-Dawley rats, with all doses being clinically relevant. The experimental design of the project consisted of two different protocols. One was to investigate the effect of DOX on the time course of Pgp-ATPase activity, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, and DOX concentration in the heart, liver, and kidneys of TAM-pretreated animals; the other protocol was to study the effect of TAM pretreatment on the disposition of DOX in the body by investigating its time course in plasma, urine and bile.
The simultaneous curve fitting of plasma data with urine and bile data with the help of the related pharmacokinetic equations provided the calculated parameters and constants. The first-order rate constants between the central and the myocardial compartments (k(1H) and k(H1)) were decreased in the TAM-treated group. The treatment also significantly reduced the k(1H)/k(H1) ratio in comparison to that of the control group. The first-order biliary elimination rate constant (k(b)) was significantly decreased (29%) in the TAM-treated group. The reduction was estimated in comparison with that of the control group. This reduction could be attributed to the inhibitory effect of TAM on Pgp located on biliary canicular membranes. The initial reduction of Pgp activity in TAM-treated group was at 60% of the basal level. The activity declined and reached a plateau at 20% of the basal activity after 6 h and remained at that level for 24 h. The area under the curves of Pgp-ATPase activity time (AUC(Activity 0-24)) following DOX administration in TAM-treated group was significantly lower than that of the control group, indicating an overall inhibitory effect of TAM on Pgp-ATPase activity under the protocol of this study. The area under the curves of the SERCA activity-time curve following DOX administration in TAM-treated group demonstrated a 15% reduction in AUC(Activity 0-24) in comparison with that of the control group, an indication of increased toxicity. The amount of myocardial Pgp in the 24-h period following DOX administration was comparable to the control group and showed no significant d |
| doi_str_mv | 10.1007/s00280-005-1001-8 |
| format | Article |
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TAM was administered daily for 11 days before the administration of DOX in male Sprague-Dawley rats, with all doses being clinically relevant. The experimental design of the project consisted of two different protocols. One was to investigate the effect of DOX on the time course of Pgp-ATPase activity, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, and DOX concentration in the heart, liver, and kidneys of TAM-pretreated animals; the other protocol was to study the effect of TAM pretreatment on the disposition of DOX in the body by investigating its time course in plasma, urine and bile.
The simultaneous curve fitting of plasma data with urine and bile data with the help of the related pharmacokinetic equations provided the calculated parameters and constants. The first-order rate constants between the central and the myocardial compartments (k(1H) and k(H1)) were decreased in the TAM-treated group. The treatment also significantly reduced the k(1H)/k(H1) ratio in comparison to that of the control group. The first-order biliary elimination rate constant (k(b)) was significantly decreased (29%) in the TAM-treated group. The reduction was estimated in comparison with that of the control group. This reduction could be attributed to the inhibitory effect of TAM on Pgp located on biliary canicular membranes. The initial reduction of Pgp activity in TAM-treated group was at 60% of the basal level. The activity declined and reached a plateau at 20% of the basal activity after 6 h and remained at that level for 24 h. The area under the curves of Pgp-ATPase activity time (AUC(Activity 0-24)) following DOX administration in TAM-treated group was significantly lower than that of the control group, indicating an overall inhibitory effect of TAM on Pgp-ATPase activity under the protocol of this study. The area under the curves of the SERCA activity-time curve following DOX administration in TAM-treated group demonstrated a 15% reduction in AUC(Activity 0-24) in comparison with that of the control group, an indication of increased toxicity. The amount of myocardial Pgp in the 24-h period following DOX administration was comparable to the control group and showed no significant deviation from the basal levels of the protein.
The effect of TAM on DOX accumulation in the myocardial tissue and the increase in cardiotoxicity can be related to the net inhibitory effect of TAM on the efflux activity of Pgp in the heart. The results of the present study supported the hypothesis of the project that multiple regimen pretreatment with Pgp modulator TAM increases the DOX accumulation in the heart and promotes DOX-induced cardiotoxicity.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-005-1001-8</identifier><identifier>PMID: 15937726</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Animals ; Antibiotics, Antineoplastic - blood ; Antibiotics, Antineoplastic - pharmacokinetics ; Antibiotics, Antineoplastic - urine ; Antineoplastic agents ; Antineoplastic Agents, Hormonal - pharmacology ; Area Under Curve ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Bile - chemistry ; Bile - metabolism ; Biological and medical sciences ; Calcium-Transporting ATPases - metabolism ; Doxorubicin - blood ; Doxorubicin - pharmacokinetics ; Doxorubicin - urine ; Kidney - chemistry ; Kidney - metabolism ; Liver - chemistry ; Liver - metabolism ; Male ; Medical sciences ; Models, Biological ; Myocardium - chemistry ; Myocardium - metabolism ; Pharmacology. Drug treatments ; Rats ; Rats, Sprague-Dawley ; Tamoxifen - administration & dosage ; Tamoxifen - pharmacology</subject><ispartof>Cancer chemotherapy and pharmacology, 2005-11, Vol.56 (5), p.497-509</ispartof><rights>2005 INIST-CNRS</rights><rights>Springer-Verlag 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-4ee0849159b0f30d19a6cc96ef5780196c5e0ee0a1d364d5df1edb757c17bd163</citedby><cites>FETCH-LOGICAL-c356t-4ee0849159b0f30d19a6cc96ef5780196c5e0ee0a1d364d5df1edb757c17bd163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17084730$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15937726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DARVARI, Ramin</creatorcontrib><creatorcontrib>BOROUJERDI, Mehdi</creatorcontrib><title>Investigation of the influence of modulation of P-glycoprotein by a multiple dosing regimen of tamoxifen on the pharmacokinetics and toxicodynamics of doxorubicin</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><description>The in vivo effect of modulators of P-glycoprotein (Pgp) on organ accumulation of substrates of Pgp has not been fully investigated. We investigated the influence of a Pgp modulator (tamoxifen, TAM) on the pharmacokinetics and toxicodynamics of a Pgp substrate (doxorubicin, DOX) in rats.
TAM was administered daily for 11 days before the administration of DOX in male Sprague-Dawley rats, with all doses being clinically relevant. The experimental design of the project consisted of two different protocols. One was to investigate the effect of DOX on the time course of Pgp-ATPase activity, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, and DOX concentration in the heart, liver, and kidneys of TAM-pretreated animals; the other protocol was to study the effect of TAM pretreatment on the disposition of DOX in the body by investigating its time course in plasma, urine and bile.
The simultaneous curve fitting of plasma data with urine and bile data with the help of the related pharmacokinetic equations provided the calculated parameters and constants. The first-order rate constants between the central and the myocardial compartments (k(1H) and k(H1)) were decreased in the TAM-treated group. The treatment also significantly reduced the k(1H)/k(H1) ratio in comparison to that of the control group. The first-order biliary elimination rate constant (k(b)) was significantly decreased (29%) in the TAM-treated group. The reduction was estimated in comparison with that of the control group. This reduction could be attributed to the inhibitory effect of TAM on Pgp located on biliary canicular membranes. The initial reduction of Pgp activity in TAM-treated group was at 60% of the basal level. The activity declined and reached a plateau at 20% of the basal activity after 6 h and remained at that level for 24 h. The area under the curves of Pgp-ATPase activity time (AUC(Activity 0-24)) following DOX administration in TAM-treated group was significantly lower than that of the control group, indicating an overall inhibitory effect of TAM on Pgp-ATPase activity under the protocol of this study. The area under the curves of the SERCA activity-time curve following DOX administration in TAM-treated group demonstrated a 15% reduction in AUC(Activity 0-24) in comparison with that of the control group, an indication of increased toxicity. The amount of myocardial Pgp in the 24-h period following DOX administration was comparable to the control group and showed no significant deviation from the basal levels of the protein.
The effect of TAM on DOX accumulation in the myocardial tissue and the increase in cardiotoxicity can be related to the net inhibitory effect of TAM on the efflux activity of Pgp in the heart. The results of the present study supported the hypothesis of the project that multiple regimen pretreatment with Pgp modulator TAM increases the DOX accumulation in the heart and promotes DOX-induced cardiotoxicity.</description><subject>Animals</subject><subject>Antibiotics, Antineoplastic - blood</subject><subject>Antibiotics, Antineoplastic - pharmacokinetics</subject><subject>Antibiotics, Antineoplastic - urine</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents, Hormonal - pharmacology</subject><subject>Area Under Curve</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Bile - chemistry</subject><subject>Bile - metabolism</subject><subject>Biological and medical sciences</subject><subject>Calcium-Transporting ATPases - metabolism</subject><subject>Doxorubicin - blood</subject><subject>Doxorubicin - pharmacokinetics</subject><subject>Doxorubicin - urine</subject><subject>Kidney - chemistry</subject><subject>Kidney - metabolism</subject><subject>Liver - chemistry</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Models, Biological</subject><subject>Myocardium - chemistry</subject><subject>Myocardium - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Tamoxifen - administration & dosage</subject><subject>Tamoxifen - pharmacology</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpFkcFu3CAURVHVKpmk-YBuKlSpS9qHMcZeRlHaRIrULtq1heExIbVhAnaU-Z1-aXFnlKzQfZx30eUS8oHDFw6gvmaAqgUGIFnRnLVvyIbXomLQ1uIt2YCoayYV1KfkLOcHAKi5ECfklMtOKFU1G_L3Njxhnv1Wzz4GGh2d75H64MYFg8F1MEW7jC_XP9l23Ju4S3FGH-iwp5pOyzj73YjUxuzDlibc-gkPbnqKz96tIvy33t3rNGkT__iAszeZ6mDpXBgT7T7oaR2VPRufY1oGb3x4T945PWa8OJ7n5Pe3619XN-zux_fbq8s7ZoRsZlYjlthdiTaAE2B5pxtjugadVC3wrjESoTCaW9HUVlrH0Q5KKsPVYHkjzsmng2_J9riUT-kf4pJCebKvuJBVB3KF-AEyKeac0PW75Ced9j2Hfi2lP5TSl1JWzfu27Hw8Gi_DhPZ149hCAT4fAZ2NHl3Swfj8yqkSTAkQ_wBubJhq</recordid><startdate>20051101</startdate><enddate>20051101</enddate><creator>DARVARI, Ramin</creator><creator>BOROUJERDI, Mehdi</creator><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</scope><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>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20051101</creationdate><title>Investigation of the influence of modulation of P-glycoprotein by a multiple dosing regimen of tamoxifen on the pharmacokinetics and toxicodynamics of doxorubicin</title><author>DARVARI, Ramin ; BOROUJERDI, Mehdi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-4ee0849159b0f30d19a6cc96ef5780196c5e0ee0a1d364d5df1edb757c17bd163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Antibiotics, Antineoplastic - blood</topic><topic>Antibiotics, Antineoplastic - pharmacokinetics</topic><topic>Antibiotics, Antineoplastic - urine</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents, Hormonal - pharmacology</topic><topic>Area Under Curve</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>Bile - chemistry</topic><topic>Bile - metabolism</topic><topic>Biological and medical sciences</topic><topic>Calcium-Transporting ATPases - metabolism</topic><topic>Doxorubicin - blood</topic><topic>Doxorubicin - pharmacokinetics</topic><topic>Doxorubicin - urine</topic><topic>Kidney - chemistry</topic><topic>Kidney - metabolism</topic><topic>Liver - chemistry</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Models, Biological</topic><topic>Myocardium - chemistry</topic><topic>Myocardium - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Tamoxifen - administration & dosage</topic><topic>Tamoxifen - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DARVARI, Ramin</creatorcontrib><creatorcontrib>BOROUJERDI, Mehdi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DARVARI, Ramin</au><au>BOROUJERDI, Mehdi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Investigation of the influence of modulation of P-glycoprotein by a multiple dosing regimen of tamoxifen on the pharmacokinetics and toxicodynamics of doxorubicin</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2005-11-01</date><risdate>2005</risdate><volume>56</volume><issue>5</issue><spage>497</spage><epage>509</epage><pages>497-509</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>The in vivo effect of modulators of P-glycoprotein (Pgp) on organ accumulation of substrates of Pgp has not been fully investigated. We investigated the influence of a Pgp modulator (tamoxifen, TAM) on the pharmacokinetics and toxicodynamics of a Pgp substrate (doxorubicin, DOX) in rats.
TAM was administered daily for 11 days before the administration of DOX in male Sprague-Dawley rats, with all doses being clinically relevant. The experimental design of the project consisted of two different protocols. One was to investigate the effect of DOX on the time course of Pgp-ATPase activity, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA) activity, and DOX concentration in the heart, liver, and kidneys of TAM-pretreated animals; the other protocol was to study the effect of TAM pretreatment on the disposition of DOX in the body by investigating its time course in plasma, urine and bile.
The simultaneous curve fitting of plasma data with urine and bile data with the help of the related pharmacokinetic equations provided the calculated parameters and constants. The first-order rate constants between the central and the myocardial compartments (k(1H) and k(H1)) were decreased in the TAM-treated group. The treatment also significantly reduced the k(1H)/k(H1) ratio in comparison to that of the control group. The first-order biliary elimination rate constant (k(b)) was significantly decreased (29%) in the TAM-treated group. The reduction was estimated in comparison with that of the control group. This reduction could be attributed to the inhibitory effect of TAM on Pgp located on biliary canicular membranes. The initial reduction of Pgp activity in TAM-treated group was at 60% of the basal level. The activity declined and reached a plateau at 20% of the basal activity after 6 h and remained at that level for 24 h. The area under the curves of Pgp-ATPase activity time (AUC(Activity 0-24)) following DOX administration in TAM-treated group was significantly lower than that of the control group, indicating an overall inhibitory effect of TAM on Pgp-ATPase activity under the protocol of this study. The area under the curves of the SERCA activity-time curve following DOX administration in TAM-treated group demonstrated a 15% reduction in AUC(Activity 0-24) in comparison with that of the control group, an indication of increased toxicity. The amount of myocardial Pgp in the 24-h period following DOX administration was comparable to the control group and showed no significant deviation from the basal levels of the protein.
The effect of TAM on DOX accumulation in the myocardial tissue and the increase in cardiotoxicity can be related to the net inhibitory effect of TAM on the efflux activity of Pgp in the heart. The results of the present study supported the hypothesis of the project that multiple regimen pretreatment with Pgp modulator TAM increases the DOX accumulation in the heart and promotes DOX-induced cardiotoxicity.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>15937726</pmid><doi>10.1007/s00280-005-1001-8</doi><tpages>13</tpages></addata></record> |
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| subjects | Animals Antibiotics, Antineoplastic - blood Antibiotics, Antineoplastic - pharmacokinetics Antibiotics, Antineoplastic - urine Antineoplastic agents Antineoplastic Agents, Hormonal - pharmacology Area Under Curve ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism Bile - chemistry Bile - metabolism Biological and medical sciences Calcium-Transporting ATPases - metabolism Doxorubicin - blood Doxorubicin - pharmacokinetics Doxorubicin - urine Kidney - chemistry Kidney - metabolism Liver - chemistry Liver - metabolism Male Medical sciences Models, Biological Myocardium - chemistry Myocardium - metabolism Pharmacology. Drug treatments Rats Rats, Sprague-Dawley Tamoxifen - administration & dosage Tamoxifen - pharmacology |
| title | Investigation of the influence of modulation of P-glycoprotein by a multiple dosing regimen of tamoxifen on the pharmacokinetics and toxicodynamics of doxorubicin |
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