Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid
Purpose Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in t...
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| Veröffentlicht in: | European journal of clinical pharmacology 2012-06, Vol.68 (6), p.913-922 |
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| container_title | European journal of clinical pharmacology |
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| creator | Rother, A. Glander, P. Vitt, E. Czock, D. von Ahsen, N. Armstrong, V. W. Oellerich, M. Budde, K. Feneberg, R. Tönshoff, B. Weber, L. T. |
| description | Purpose
Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.
Methods
We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0–17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.
Results
Inosine 5’-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42–184] μmol/s/mol AMP), school-age children (61 [30–153]), adolescents (83 [43–154]) and healthy adults (83 [26–215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.
Conclusions
In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation. |
| doi_str_mv | 10.1007/s00228-011-1203-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1013615918</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2660892101</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-55efcb591f1a8181491dc2348322f89bca77e1a2204574486bb65a75affa06fd3</originalsourceid><addsrcrecordid>eNp1kM1uGyEURlGVqnHSPkA3FVLUJe29DMxPdlGUNpEiddOuR3cYsIlsmMBMJb99sOy22XQFiPN9Fw5jHxG-IEDzNQNI2QpAFCihEuoNW6GqpEBQeMZWABWKumvgnF3k_ASAuoPqHTuXUjZKgVqx5SHE7IPluxjitIl52tBs-Wg3-zHFtQ2ULScz-99-3nMf-ER29DQnb_I1p7UVyW5LYuTJrpey8zFwCodjnmIo4Tny3d6Ubhvi1ptS5sf37K2jbbYfTusl-_Xt7uftvXj88f3h9uZRGAVyFlpbZwbdoUNqsUXV4WhkpdpKStd2g6GmsUhSgtLlP209DLWmRpNzBLUbq0t2deydUnxebJ77p7ikUEb2CFjVxQe2hcIjZVLMOVnXT8nvKO0L1B9E90fRfRHdH0T3qmQ-nZqXYWfHv4k_Zgvw-QRQNrR1iYLx-R-nO6lqqQsnj1wuV2Ft0-sn_m_6C02ulvM</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1013615918</pqid></control><display><type>article</type><title>Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Rother, A. ; Glander, P. ; Vitt, E. ; Czock, D. ; von Ahsen, N. ; Armstrong, V. W. ; Oellerich, M. ; Budde, K. ; Feneberg, R. ; Tönshoff, B. ; Weber, L. T.</creator><creatorcontrib>Rother, A. ; Glander, P. ; Vitt, E. ; Czock, D. ; von Ahsen, N. ; Armstrong, V. W. ; Oellerich, M. ; Budde, K. ; Feneberg, R. ; Tönshoff, B. ; Weber, L. T.</creatorcontrib><description>Purpose
Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.
Methods
We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0–17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.
Results
Inosine 5’-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42–184] μmol/s/mol AMP), school-age children (61 [30–153]), adolescents (83 [43–154]) and healthy adults (83 [26–215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.
Conclusions
In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-011-1203-4</identifier><identifier>PMID: 22274404</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adolescent ; Adult ; Age Factors ; Biological and medical sciences ; Biomarkers ; Biomedical and Life Sciences ; Biomedicine ; Child ; Child, Preschool ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Enzymes ; Female ; Humans ; Immunomodulators ; IMP Dehydrogenase - blood ; IMP Dehydrogenase - metabolism ; Kidney - drug effects ; Kidney - metabolism ; Kidney Transplantation ; Kidneys ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - enzymology ; Leukocytes, Mononuclear - metabolism ; Male ; Medical sciences ; Mycophenolic Acid - antagonists & inhibitors ; Mycophenolic Acid - pharmacokinetics ; Mycophenolic Acid - pharmacology ; Pediatrics ; Pharmacodynamics ; Pharmacology ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Transplants & implants</subject><ispartof>European journal of clinical pharmacology, 2012-06, Vol.68 (6), p.913-922</ispartof><rights>Springer-Verlag 2012</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-55efcb591f1a8181491dc2348322f89bca77e1a2204574486bb65a75affa06fd3</citedby><cites>FETCH-LOGICAL-c402t-55efcb591f1a8181491dc2348322f89bca77e1a2204574486bb65a75affa06fd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00228-011-1203-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00228-011-1203-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25924625$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22274404$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rother, A.</creatorcontrib><creatorcontrib>Glander, P.</creatorcontrib><creatorcontrib>Vitt, E.</creatorcontrib><creatorcontrib>Czock, D.</creatorcontrib><creatorcontrib>von Ahsen, N.</creatorcontrib><creatorcontrib>Armstrong, V. W.</creatorcontrib><creatorcontrib>Oellerich, M.</creatorcontrib><creatorcontrib>Budde, K.</creatorcontrib><creatorcontrib>Feneberg, R.</creatorcontrib><creatorcontrib>Tönshoff, B.</creatorcontrib><creatorcontrib>Weber, L. T.</creatorcontrib><title>Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><addtitle>Eur J Clin Pharmacol</addtitle><description>Purpose
Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.
Methods
We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0–17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.
Results
Inosine 5’-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42–184] μmol/s/mol AMP), school-age children (61 [30–153]), adolescents (83 [43–154]) and healthy adults (83 [26–215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.
Conclusions
In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Age Factors</subject><subject>Biological and medical sciences</subject><subject>Biomarkers</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzymes</subject><subject>Female</subject><subject>Humans</subject><subject>Immunomodulators</subject><subject>IMP Dehydrogenase - blood</subject><subject>IMP Dehydrogenase - metabolism</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney Transplantation</subject><subject>Kidneys</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - enzymology</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mycophenolic Acid - antagonists & inhibitors</subject><subject>Mycophenolic Acid - pharmacokinetics</subject><subject>Mycophenolic Acid - pharmacology</subject><subject>Pediatrics</subject><subject>Pharmacodynamics</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Transplants & implants</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kM1uGyEURlGVqnHSPkA3FVLUJe29DMxPdlGUNpEiddOuR3cYsIlsmMBMJb99sOy22XQFiPN9Fw5jHxG-IEDzNQNI2QpAFCihEuoNW6GqpEBQeMZWABWKumvgnF3k_ASAuoPqHTuXUjZKgVqx5SHE7IPluxjitIl52tBs-Wg3-zHFtQ2ULScz-99-3nMf-ER29DQnb_I1p7UVyW5LYuTJrpey8zFwCodjnmIo4Tny3d6Ubhvi1ptS5sf37K2jbbYfTusl-_Xt7uftvXj88f3h9uZRGAVyFlpbZwbdoUNqsUXV4WhkpdpKStd2g6GmsUhSgtLlP209DLWmRpNzBLUbq0t2deydUnxebJ77p7ikUEb2CFjVxQe2hcIjZVLMOVnXT8nvKO0L1B9E90fRfRHdH0T3qmQ-nZqXYWfHv4k_Zgvw-QRQNrR1iYLx-R-nO6lqqQsnj1wuV2Ft0-sn_m_6C02ulvM</recordid><startdate>20120601</startdate><enddate>20120601</enddate><creator>Rother, A.</creator><creator>Glander, P.</creator><creator>Vitt, E.</creator><creator>Czock, D.</creator><creator>von Ahsen, N.</creator><creator>Armstrong, V. W.</creator><creator>Oellerich, M.</creator><creator>Budde, K.</creator><creator>Feneberg, R.</creator><creator>Tönshoff, B.</creator><creator>Weber, L. T.</creator><general>Springer-Verlag</general><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>7RV</scope><scope>7TK</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</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>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20120601</creationdate><title>Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid</title><author>Rother, A. ; Glander, P. ; Vitt, E. ; Czock, D. ; von Ahsen, N. ; Armstrong, V. W. ; Oellerich, M. ; Budde, K. ; Feneberg, R. ; Tönshoff, B. ; Weber, L. T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-55efcb591f1a8181491dc2348322f89bca77e1a2204574486bb65a75affa06fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Age Factors</topic><topic>Biological and medical sciences</topic><topic>Biomarkers</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzymes</topic><topic>Female</topic><topic>Humans</topic><topic>Immunomodulators</topic><topic>IMP Dehydrogenase - blood</topic><topic>IMP Dehydrogenase - metabolism</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>Kidney Transplantation</topic><topic>Kidneys</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - enzymology</topic><topic>Leukocytes, Mononuclear - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mycophenolic Acid - antagonists & inhibitors</topic><topic>Mycophenolic Acid - pharmacokinetics</topic><topic>Mycophenolic Acid - pharmacology</topic><topic>Pediatrics</topic><topic>Pharmacodynamics</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Transplants & implants</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rother, A.</creatorcontrib><creatorcontrib>Glander, P.</creatorcontrib><creatorcontrib>Vitt, E.</creatorcontrib><creatorcontrib>Czock, D.</creatorcontrib><creatorcontrib>von Ahsen, N.</creatorcontrib><creatorcontrib>Armstrong, V. W.</creatorcontrib><creatorcontrib>Oellerich, M.</creatorcontrib><creatorcontrib>Budde, K.</creatorcontrib><creatorcontrib>Feneberg, R.</creatorcontrib><creatorcontrib>Tönshoff, B.</creatorcontrib><creatorcontrib>Weber, L. T.</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>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS 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>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>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</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>European journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rother, A.</au><au>Glander, P.</au><au>Vitt, E.</au><au>Czock, D.</au><au>von Ahsen, N.</au><au>Armstrong, V. W.</au><au>Oellerich, M.</au><au>Budde, K.</au><au>Feneberg, R.</au><au>Tönshoff, B.</au><au>Weber, L. T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid</atitle><jtitle>European journal of clinical pharmacology</jtitle><stitle>Eur J Clin Pharmacol</stitle><addtitle>Eur J Clin Pharmacol</addtitle><date>2012-06-01</date><risdate>2012</risdate><volume>68</volume><issue>6</issue><spage>913</spage><epage>922</epage><pages>913-922</pages><issn>0031-6970</issn><eissn>1432-1041</eissn><abstract>Purpose
Since many drug targets and metabolizing enzymes are developmentally regulated, we investigated a potential comparable regulation of inosine 5’-monophosphate dehydrogenase (IMPDH) activity that has recently been advocated as a pharmacodynamic biomarker of mycophenolic acid (MPA) effects in the paediatric population. Since the field of pharmacodynamic monitoring of MPA is evolving, we also analyzed the response of IMPDH activity on MPA in children vs adolescents after renal transplantation.
Methods
We analyzed IMPDH activity in peripheral blood mononuclear cells (PBMCs) in 79 healthy children aged 2.0–17.9 years in comparison to 106 healthy adults. Pharmacokinetic/pharmacodynamic profiles of MPA and IMPDH over 6 or 12 h after mycophenolate mofetil dosing were performed in 17 paediatric renal transplant recipients. IMPDH activity was measured by HPLC and normalized to the adenosine monophosphate (AMP) content of the cells, MPA plasma concentrations were measured by HPLC.
Results
Inosine 5’-monophosphate dehydrogenase activity displayed a high inter-individual variability (coefficient of variation 40.2%) throughout the entire age range studied. Median IMPDH did not differ significantly in healthy pre-school children (82 [range, 42–184] μmol/s/mol AMP), school-age children (61 [30–153]), adolescents (83 [43–154]) and healthy adults (83 [26–215]). Similar to adults, IMPDH activity in children and adolescents was inversely correlated with MPA plasma concentration.
Conclusions
In conclusion, our data do not show a pronounced developmental regulation of IMPDH activity in PBMCs in the paediatric population and there is a comparable inhibition of IMPDH activity by MPA in children and adolescents after renal transplantation.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>22274404</pmid><doi>10.1007/s00228-011-1203-4</doi><tpages>10</tpages></addata></record> |
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| subjects | Adolescent Adult Age Factors Biological and medical sciences Biomarkers Biomedical and Life Sciences Biomedicine Child Child, Preschool Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Enzymes Female Humans Immunomodulators IMP Dehydrogenase - blood IMP Dehydrogenase - metabolism Kidney - drug effects Kidney - metabolism Kidney Transplantation Kidneys Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - enzymology Leukocytes, Mononuclear - metabolism Male Medical sciences Mycophenolic Acid - antagonists & inhibitors Mycophenolic Acid - pharmacokinetics Mycophenolic Acid - pharmacology Pediatrics Pharmacodynamics Pharmacology Pharmacology. Drug treatments Pharmacology/Toxicology Transplants & implants |
| title | Inosine monophosphate dehydrogenase activity in paediatrics: age-related regulation and response to mycophenolic acid |
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