Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients
Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is media...
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| Veröffentlicht in: | Journal of clinical pharmacology 2021-12, Vol.61 (12), p.1592-1605 |
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| creator | Brazeau, Daniel Meaney, Calvin J. Consiglio, Joseph D. Wilding, Gregory E. Cooper, Louise M. Venuto, Rocco C. Tornatore, Kathleen M. |
| description | Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance‐associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes ‐24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross‐sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0‐12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h. The wild‐type haplotype ABCC2 CGC had greater mycophenolic acid AUC0‐12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine‐mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment. |
| doi_str_mv | 10.1002/jcph.1932 |
| format | Article |
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This conversion by enterohepatic circulation is mediated by the multidrug resistance‐associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes ‐24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross‐sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0‐12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h. The wild‐type haplotype ABCC2 CGC had greater mycophenolic acid AUC0‐12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine‐mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.</description><identifier>ISSN: 0091-2700</identifier><identifier>ISSN: 1552-4604</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.1932</identifier><identifier>PMID: 34169529</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>ABCC2 haplotypes ; Acids ; Adult ; Area Under Curve ; Calcineurin ; calcineurin inhibitor ; Calcineurin inhibitors ; Calcineurin Inhibitors - administration & dosage ; Calcineurin Inhibitors - pharmacology ; Cross-Sectional Studies ; Cyclosporins ; enterohepatic circulation ; Enterohepatic Circulation - physiology ; Female ; Genotypes ; Haplotypes ; Humans ; Immunosuppressive Agents - administration & dosage ; Immunosuppressive Agents - pharmacokinetics ; Immunosuppressive Agents - pharmacology ; Kidney Transplantation ; Kidney transplants ; Male ; Middle Aged ; Multidrug resistance ; Multidrug Resistance-Associated Protein 2 - genetics ; Mycophenolic acid ; Mycophenolic Acid - pharmacokinetics ; Pharmacokinetics ; Phenotypes ; Prospective Studies ; Tacrolimus ; transporters</subject><ispartof>Journal of clinical pharmacology, 2021-12, Vol.61 (12), p.1592-1605</ispartof><rights>2021, The American College of Clinical Pharmacology</rights><rights>2021, The American College of Clinical Pharmacology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5092-313d88f4226cb2a14c8f9aea946dd8949e824d490635cef8cf4093c182f8db03</citedby><cites>FETCH-LOGICAL-c5092-313d88f4226cb2a14c8f9aea946dd8949e824d490635cef8cf4093c182f8db03</cites><orcidid>0000-0003-2213-693X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcph.1932$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcph.1932$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34169529$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brazeau, Daniel</creatorcontrib><creatorcontrib>Meaney, Calvin J.</creatorcontrib><creatorcontrib>Consiglio, Joseph D.</creatorcontrib><creatorcontrib>Wilding, Gregory E.</creatorcontrib><creatorcontrib>Cooper, Louise M.</creatorcontrib><creatorcontrib>Venuto, Rocco C.</creatorcontrib><creatorcontrib>Tornatore, Kathleen M.</creatorcontrib><title>Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients</title><title>Journal of clinical pharmacology</title><addtitle>J Clin Pharmacol</addtitle><description>Mycophenolic acid exhibits significant interpatient pharmacokinetic variability attributed to factors including race, sex, concurrent medications, and enterohepatic circulation of the mycophenolic acid glucuronide metabolite to mycophenolic acid. This conversion by enterohepatic circulation is mediated by the multidrug resistance‐associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes ‐24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross‐sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0‐12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h. The wild‐type haplotype ABCC2 CGC had greater mycophenolic acid AUC0‐12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine‐mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.</description><subject>ABCC2 haplotypes</subject><subject>Acids</subject><subject>Adult</subject><subject>Area Under Curve</subject><subject>Calcineurin</subject><subject>calcineurin inhibitor</subject><subject>Calcineurin inhibitors</subject><subject>Calcineurin Inhibitors - administration & dosage</subject><subject>Calcineurin Inhibitors - pharmacology</subject><subject>Cross-Sectional Studies</subject><subject>Cyclosporins</subject><subject>enterohepatic circulation</subject><subject>Enterohepatic Circulation - physiology</subject><subject>Female</subject><subject>Genotypes</subject><subject>Haplotypes</subject><subject>Humans</subject><subject>Immunosuppressive Agents - administration & dosage</subject><subject>Immunosuppressive Agents - pharmacokinetics</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Kidney Transplantation</subject><subject>Kidney transplants</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Multidrug resistance</subject><subject>Multidrug Resistance-Associated Protein 2 - genetics</subject><subject>Mycophenolic acid</subject><subject>Mycophenolic Acid - pharmacokinetics</subject><subject>Pharmacokinetics</subject><subject>Phenotypes</subject><subject>Prospective Studies</subject><subject>Tacrolimus</subject><subject>transporters</subject><issn>0091-2700</issn><issn>1552-4604</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFuEzEQhq0K1Kahh74AssQFDtvaXntjX5DCCgi0iIrmbjneWeLg2Iu9odq3Z0PaCpB6msN8-mZ-_QidU3JBCWGXG9utL6gq2RGaUCFYwSvCn6EJIYoWbEbICTrNeUMIrbigx-ik5LRSgqkJ8vOco3WmdzHg2OL5u7pmeGE6H_uhg4z7iL8MNnZrCNE7i-fWNfhmbdLW2PjDBeidzdgFfNublQd85ZoAA14mE3LnTejxN7CucxD6_AI9b43PcHY_p2j54f2yXhTXXz9-qufXhRVEsaKkZSNlyxmr7IoZyq1slQGjeNU0UnEFkvGGK1KVwkIrbcuJKi2VrJXNipRT9Pag7XarLTR2PJ2M111yW5MGHY3T_26CW-vv8ZdWpZAVm42C1_eCFH_uIPd667IFP8aBuMuaCS6E4ny2v_XqP3QTdymM6UZKSaK4HONM0ZsDZVPMOUH7-Awlel-h3leo9xWO7Mu_v38kHzobgcsDcOc8DE-b9Of6ZvFH-RuUV6cv</recordid><startdate>202112</startdate><enddate>202112</enddate><creator>Brazeau, Daniel</creator><creator>Meaney, Calvin J.</creator><creator>Consiglio, Joseph D.</creator><creator>Wilding, Gregory E.</creator><creator>Cooper, Louise M.</creator><creator>Venuto, Rocco C.</creator><creator>Tornatore, Kathleen M.</creator><general>Wiley Subscription Services, Inc</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2213-693X</orcidid></search><sort><creationdate>202112</creationdate><title>Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients</title><author>Brazeau, Daniel ; 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This conversion by enterohepatic circulation is mediated by the multidrug resistance‐associated protein 2, encoded by ABCC2. This study investigated ABCC2 haplotype associations with mycophenolic acid pharmacokinetics in 147 stable kidney transplant recipients receiving mycophenolic acid in combination with calcineurin inhibitors. The role of the ABCC2 genotypes ‐24C>T (rs717620), 1249C>T (rs2273697), and 3972C>T (rs3740066) were evaluated in prospective, cross‐sectional pharmacokinetic studies of stable recipients receiving mycophenolic acid and either tacrolimus or cyclosporine. Haplotype phenotypic associations with mycophenolic acid pharmacokinetic parameters were computed using THESIAS (v. 3.1). Four ABCC2 haplotypes with estimated frequencies greater than 10% were identified (H1:CGC [wild type], H9:CGT, H2:CAC, H12:TGT). There were no differences in haplotype frequencies by either race or sex. There were significant associations of pharmacokinetic parameters with ABCC2 haplotypes for mycophenolic acid clearance (L/h), mycophenolic acid AUC0‐12h (mg·h/L), and the ratio of mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h. The wild‐type haplotype ABCC2 CGC had greater mycophenolic acid AUC0‐12h (P = .017), slower clearance (P = .013), and lower mycophenolic acid glucuronide to mycophenolic acid AUC0‐12h ratio (P = .047) compared with the reduced function ABCC2 haplotype CGT. These differences were most pronounced among patients receiving tacrolimus cotreatment. No phenotypic associations were found with the cyclosporine‐mycophenolic acid regimen. Variation in ABCC2 haplotypes contributes to subtherapeutic mycophenolic acid exposure and influences interpatient variability in pharmacokinetic phenotypes based on concurrent calcineurin inhibitor treatment.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34169529</pmid><doi>10.1002/jcph.1932</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0003-2213-693X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | ABCC2 haplotypes Acids Adult Area Under Curve Calcineurin calcineurin inhibitor Calcineurin inhibitors Calcineurin Inhibitors - administration & dosage Calcineurin Inhibitors - pharmacology Cross-Sectional Studies Cyclosporins enterohepatic circulation Enterohepatic Circulation - physiology Female Genotypes Haplotypes Humans Immunosuppressive Agents - administration & dosage Immunosuppressive Agents - pharmacokinetics Immunosuppressive Agents - pharmacology Kidney Transplantation Kidney transplants Male Middle Aged Multidrug resistance Multidrug Resistance-Associated Protein 2 - genetics Mycophenolic acid Mycophenolic Acid - pharmacokinetics Pharmacokinetics Phenotypes Prospective Studies Tacrolimus transporters |
| title | Association of ABCC2 Haplotypes to Mycophenolic Acid Pharmacokinetics in Stable Kidney Transplant Recipients |
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