Oral Sulfasalazine as a Clinical BCRP Probe Substrate: Pharmacokinetic Effects of Genetic Variation (C421A) and Pantoprazole Coadministration
This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolite...
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| Veröffentlicht in: | Journal of pharmaceutical sciences 2010-02, Vol.99 (2), p.1046-1062 |
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| creator | Adkison, Kimberly K. Vaidya, Soniya S. Lee, Daniel Y. Koo, Seok Hwee Li, Linghui Mehta, Amar A. Gross, Annette S. Polli, Joseph W. Humphreys, Joan E. Lou, Yu Lee, Edmund J.D. |
| description | This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolites. Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC(0–∞) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) µg h/mL, and Cmax were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) µg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1046–1062, 2010 |
| doi_str_mv | 10.1002/jps.21860 |
| format | Article |
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Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC(0–∞) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) µg h/mL, and Cmax were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) µg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1046–1062, 2010</description><identifier>ISSN: 0022-3549</identifier><identifier>ISSN: 1520-6017</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1002/jps.21860</identifier><identifier>PMID: 19569219</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>Hoboken: Elsevier Inc</publisher><subject>2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics ; ABC transporters ; Adult ; Arylamine N-Acetyltransferase - genetics ; Arylamine N-Acetyltransferase - metabolism ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters - antagonists & inhibitors ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; Biological and medical sciences ; Biotransformation ; Breast cancer ; Chromatography, High Pressure Liquid ; clinical pharmacokinetics ; Cross-Over Studies ; drug interactions ; Enzyme Inhibitors - pharmacokinetics ; Famotidine ; Famotidine - pharmacokinetics ; General pharmacology ; Genetic diversity ; Genotype ; Genotypes ; Humans ; Hydrogen-Ion Concentration ; Male ; Medical sciences ; metabolite kinetics ; Metabolites ; Middle Aged ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; pH effects ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacogenetics ; Pharmacokinetics ; Pharmacology. Drug treatments ; Polymorphism, Genetic ; Probes ; Proton Pump Inhibitors - pharmacokinetics ; Spectrophotometry, Ultraviolet ; Stomach - metabolism ; sulfasalazine ; Sulfasalazine - pharmacokinetics ; Urine ; Young Adult</subject><ispartof>Journal of pharmaceutical sciences, 2010-02, Vol.99 (2), p.1046-1062</ispartof><rights>2010 Wiley-Liss, Inc.</rights><rights>Copyright © 2009 Wiley‐Liss, Inc.</rights><rights>2015 INIST-CNRS</rights><rights>(c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5350-269987b60866fdd73225cb795c9a921d0ce1613711bc9f6c0e986032db780c1e3</citedby><cites>FETCH-LOGICAL-c5350-269987b60866fdd73225cb795c9a921d0ce1613711bc9f6c0e986032db780c1e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjps.21860$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjps.21860$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22364452$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19569219$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adkison, Kimberly K.</creatorcontrib><creatorcontrib>Vaidya, Soniya S.</creatorcontrib><creatorcontrib>Lee, Daniel Y.</creatorcontrib><creatorcontrib>Koo, Seok Hwee</creatorcontrib><creatorcontrib>Li, Linghui</creatorcontrib><creatorcontrib>Mehta, Amar A.</creatorcontrib><creatorcontrib>Gross, Annette S.</creatorcontrib><creatorcontrib>Polli, Joseph W.</creatorcontrib><creatorcontrib>Humphreys, Joan E.</creatorcontrib><creatorcontrib>Lou, Yu</creatorcontrib><creatorcontrib>Lee, Edmund J.D.</creatorcontrib><title>Oral Sulfasalazine as a Clinical BCRP Probe Substrate: Pharmacokinetic Effects of Genetic Variation (C421A) and Pantoprazole Coadministration</title><title>Journal of pharmaceutical sciences</title><addtitle>J. Pharm. Sci</addtitle><description>This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolites. Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC(0–∞) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) µg h/mL, and Cmax were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) µg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1046–1062, 2010</description><subject>2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics</subject><subject>ABC transporters</subject><subject>Adult</subject><subject>Arylamine N-Acetyltransferase - genetics</subject><subject>Arylamine N-Acetyltransferase - metabolism</subject><subject>ATP Binding Cassette Transporter, Sub-Family G, Member 2</subject><subject>ATP-Binding Cassette Transporters - antagonists & inhibitors</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Breast cancer</subject><subject>Chromatography, High Pressure Liquid</subject><subject>clinical pharmacokinetics</subject><subject>Cross-Over Studies</subject><subject>drug interactions</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Famotidine</subject><subject>Famotidine - pharmacokinetics</subject><subject>General pharmacology</subject><subject>Genetic diversity</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Male</subject><subject>Medical sciences</subject><subject>metabolite kinetics</subject><subject>Metabolites</subject><subject>Middle Aged</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>pH effects</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacogenetics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Polymorphism, Genetic</subject><subject>Probes</subject><subject>Proton Pump Inhibitors - pharmacokinetics</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Stomach - metabolism</subject><subject>sulfasalazine</subject><subject>Sulfasalazine - pharmacokinetics</subject><subject>Urine</subject><subject>Young Adult</subject><issn>0022-3549</issn><issn>1520-6017</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c1u1DAQB_AIgehSOPACyBdEe0jrj9hZc2ujskArutDycbMmzkS4TeLFzgLtO_DOmGYpF-Bkyf7NjMb_LHvM6B6jlO9frOIeZ3NF72QzJjnNFWXl3WyW3nguZKG3sgcxXlBKFZXyfrbFtFSaMz3LfpwG6MjZumshQgfXbkACkQCpOjc4m94Oq3dLsgy-xsTqOAYY8TlZfobQg_WXqWB0lhy1LdoxEt-SBU5XHyA4GJ0fyE5VcHawS2BoyBKG0a8CXPsOSeWh6dOcm65JPszutdBFfLQ5t7P3L47Oq5f5yeniVXVwklspJM250npe1orOlWqbphScS1uXWloNaa2GWmSKiZKx2upWWYo6fY7gTV3OqWUotrNnU99V8F_WGEfTu2ix62BAv46mFEIxWnCR5M5_JaNaFFIwWSS6O1EbfIwBW7MKrodwlZD5lZNJOZmbnJJ9smm7rnts_shNMAk83QCIKYU2wGBdvHWcC1UUkie3P7lvrsOrf080r5dnv0fnU0X6dfx-WwHh0qhSlNJ8fLMwn94enpcLemyOkxeTxxTIV4fBROtwsNi4kCI3jXd_WfAnYnLJHg</recordid><startdate>201002</startdate><enddate>201002</enddate><creator>Adkison, Kimberly K.</creator><creator>Vaidya, Soniya S.</creator><creator>Lee, Daniel Y.</creator><creator>Koo, Seok Hwee</creator><creator>Li, Linghui</creator><creator>Mehta, Amar A.</creator><creator>Gross, Annette S.</creator><creator>Polli, Joseph W.</creator><creator>Humphreys, Joan E.</creator><creator>Lou, Yu</creator><creator>Lee, Edmund J.D.</creator><general>Elsevier Inc</general><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>American Pharmaceutical Association</general><scope>BSCLL</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201002</creationdate><title>Oral Sulfasalazine as a Clinical BCRP Probe Substrate: Pharmacokinetic Effects of Genetic Variation (C421A) and Pantoprazole Coadministration</title><author>Adkison, Kimberly K. ; Vaidya, Soniya S. ; Lee, Daniel Y. ; Koo, Seok Hwee ; Li, Linghui ; Mehta, Amar A. ; Gross, Annette S. ; Polli, Joseph W. ; Humphreys, Joan E. ; Lou, Yu ; Lee, Edmund J.D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5350-269987b60866fdd73225cb795c9a921d0ce1613711bc9f6c0e986032db780c1e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics</topic><topic>ABC transporters</topic><topic>Adult</topic><topic>Arylamine N-Acetyltransferase - genetics</topic><topic>Arylamine N-Acetyltransferase - metabolism</topic><topic>ATP Binding Cassette Transporter, Sub-Family G, Member 2</topic><topic>ATP-Binding Cassette Transporters - antagonists & inhibitors</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Breast cancer</topic><topic>Chromatography, High Pressure Liquid</topic><topic>clinical pharmacokinetics</topic><topic>Cross-Over Studies</topic><topic>drug interactions</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Famotidine</topic><topic>Famotidine - pharmacokinetics</topic><topic>General pharmacology</topic><topic>Genetic diversity</topic><topic>Genotype</topic><topic>Genotypes</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Male</topic><topic>Medical sciences</topic><topic>metabolite kinetics</topic><topic>Metabolites</topic><topic>Middle Aged</topic><topic>Neoplasm Proteins - antagonists & inhibitors</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>pH effects</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacogenetics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Polymorphism, Genetic</topic><topic>Probes</topic><topic>Proton Pump Inhibitors - pharmacokinetics</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Stomach - metabolism</topic><topic>sulfasalazine</topic><topic>Sulfasalazine - pharmacokinetics</topic><topic>Urine</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adkison, Kimberly K.</creatorcontrib><creatorcontrib>Vaidya, Soniya S.</creatorcontrib><creatorcontrib>Lee, Daniel Y.</creatorcontrib><creatorcontrib>Koo, Seok Hwee</creatorcontrib><creatorcontrib>Li, Linghui</creatorcontrib><creatorcontrib>Mehta, Amar A.</creatorcontrib><creatorcontrib>Gross, Annette S.</creatorcontrib><creatorcontrib>Polli, Joseph W.</creatorcontrib><creatorcontrib>Humphreys, Joan E.</creatorcontrib><creatorcontrib>Lou, Yu</creatorcontrib><creatorcontrib>Lee, Edmund J.D.</creatorcontrib><collection>Istex</collection><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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Adkison, Kimberly K.</au><au>Vaidya, Soniya S.</au><au>Lee, Daniel Y.</au><au>Koo, Seok Hwee</au><au>Li, Linghui</au><au>Mehta, Amar A.</au><au>Gross, Annette S.</au><au>Polli, Joseph W.</au><au>Humphreys, Joan E.</au><au>Lou, Yu</au><au>Lee, Edmund J.D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oral Sulfasalazine as a Clinical BCRP Probe Substrate: Pharmacokinetic Effects of Genetic Variation (C421A) and Pantoprazole Coadministration</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J. Pharm. Sci</addtitle><date>2010-02</date><risdate>2010</risdate><volume>99</volume><issue>2</issue><spage>1046</spage><epage>1062</epage><pages>1046-1062</pages><issn>0022-3549</issn><issn>1520-6017</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>This study evaluated the utility of oral sulfasalazine as a probe substrate for Breast Cancer Resistance Protein (BCRP; ABCG2) activity by assessing the impact of genetic variation or coadministration of an inhibitor (pantoprazole) on plasma and urine pharmacokinetics of sulfasalazine and metabolites. Thirty-six healthy male subjects prescreened for ABCG2 421CC (reference activity), CA, and AA (lower activity) genotypes (N = 12 each) received a single 500 mg oral dose of enteric coated sulfasalazine alone, with 40 mg pantoprazole, or with 40 mg famotidine (gastrointestinal pH control) in a 3-period, single fixed sequence, crossover design. No significant difference in sulfasalazine or metabolite pharmacokinetics in 421AA or CA compared to 421CC subjects was found; however, high inter-subject variability was observed. Geometric mean (95% CI) sulfasalazine plasma AUC(0–∞) values were 32.1 (13.2, 78.1), 16.8 (7.15, 39.6) and 62.7 (33.4, 118) µg h/mL, and Cmax were 4.01 (1.62, 9.92), 1.70 (0.66, 4.40), and 6.86 (3.61, 13.0) µg/mL for CC, CA, and AA subjects, respectively. Pantoprazole and famotidine did not affect sulfasalazine pharmacokinetics in any genotypic cohort. These results suggest that the pharmacokinetics of oral, enteric-coated 500 mg sulfasalazine are not sufficiently sensitive to ABCG2 genetic variation or inhibitors to be useful as a clinical probe substrate of BCRP activity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:1046–1062, 2010</abstract><cop>Hoboken</cop><pub>Elsevier Inc</pub><pmid>19569219</pmid><doi>10.1002/jps.21860</doi><tpages>17</tpages></addata></record> |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete; Alma/SFX Local Collection |
| subjects | 2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics ABC transporters Adult Arylamine N-Acetyltransferase - genetics Arylamine N-Acetyltransferase - metabolism ATP Binding Cassette Transporter, Sub-Family G, Member 2 ATP-Binding Cassette Transporters - antagonists & inhibitors ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism Biological and medical sciences Biotransformation Breast cancer Chromatography, High Pressure Liquid clinical pharmacokinetics Cross-Over Studies drug interactions Enzyme Inhibitors - pharmacokinetics Famotidine Famotidine - pharmacokinetics General pharmacology Genetic diversity Genotype Genotypes Humans Hydrogen-Ion Concentration Male Medical sciences metabolite kinetics Metabolites Middle Aged Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - genetics Neoplasm Proteins - metabolism pH effects Pharmaceutical technology. Pharmaceutical industry Pharmacogenetics Pharmacokinetics Pharmacology. Drug treatments Polymorphism, Genetic Probes Proton Pump Inhibitors - pharmacokinetics Spectrophotometry, Ultraviolet Stomach - metabolism sulfasalazine Sulfasalazine - pharmacokinetics Urine Young Adult |
| title | Oral Sulfasalazine as a Clinical BCRP Probe Substrate: Pharmacokinetic Effects of Genetic Variation (C421A) and Pantoprazole Coadministration |
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