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AuthorAbdel-Kahaar, Emaaddc.contributor.author
AuthorWinter, Stefandc.contributor.author
AuthorTremmel, Romandc.contributor.author
AuthorSchaeffeler, Elkedc.contributor.author
AuthorOlbricht, Christoph J.dc.contributor.author
AuthorWieland, Eberharddc.contributor.author
AuthorSchwab, Matthiasdc.contributor.author
AuthorShipkova, Mariadc.contributor.author
AuthorJäger, Simon U.dc.contributor.author
Date of accession2021-06-10T09:47:34Zdc.date.accessioned
Available in OPARU since2021-06-10T09:47:34Zdc.date.available
Date of first publication2019-09-26dc.date.issued
AbstractBackground: Although there is evidence that the CYP3A4*22 variant should be considered in tacrolimus dosing in renal transplantation, its impact beyond tacrolimus dose requirements remains controversial. Methods: In a cohort of 121 kidney transplant recipients, we analyzed the CYP3A4*1B, CYP3A4*22, and CYP3A5*3 alleles and the ABCB1 variants 1236C>T, 2677G>T/A, and 3435C>T for their impact on exposure and dose requirement. Relevant clinical outcome measures such as acute rejection within the first year after transplantation, delayed graft function, and renal function at discharge (estimated glomerular filtration rate) were evaluated. Results: Extensive metabolizer (n = 17, CYP3A4*1/*1 carriers with at least one CYP3A5*1 allele) showed significantly higher tacrolimus dose requirement (P = 0.004) compared with both intermediate metabolizer (IM, n = 93, CYP3A5*3/*3 plus CYP3A4*1/*1 or CYP3A4*22 carriers plus one CYP3A5*1 allele), and poor metabolizer (n = 11, CYP3A4*22 allele in combination with CYP3A5*3/*3) after onset of therapy. Significantly higher dose requirement was observed in CYP3A5 expressers (P = 0.046) compared with non-expressers again at onset of therapy. Using the log additive genetic model, the area under the curve for the total observation period up to 16 days was significantly associated with the CYP3A5*3 genotype (P = 3.34 × 10-4) as well as with the IM or extensive metabolizer phenotype (P = 1.54 × 10-4), even after adjustment for multiple testing. Heterozygous carriers for CYP3A4*22 showed significantly higher areas under the curve than the CYP3A4*1/*1 genotype in the second week post-transplantation (adjusted P = 0.016). Regarding clinical outcomes, acute rejection was significantly associated with human leukocyte antigen mismatch (≥3 alleles; OR = 12.14, 95% CI 1.76, 525.21, P = 0.019 after correction for multiple testing). Graft recipients from deceased donors showed higher incidende of delayed graft function (OR 7.15, 95% CI 2.23, 30.46, adjusted P = 0.0008) and a lower estimated glomerular filtration rate at discharge (P = 0.0001). Tested CYP3A4 or CYP3A5 variants did not show any effects on clinical outcome parameters. ABCB1 variants did neither impact on pharmacokinetics nor on clinical endpoints. Conclusion: At our transplantation center, both CYP3A5*3 and, to a lesser extent, CYP3A4*22 affect tacrolimus pharmacokinetics early after onset of therapy with consequences for steady-state treatment in routine clinical practice.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseCC BY 4.0 Internationaldc.rights
Link to license texthttps://creativecommons.org/licenses/by/4.0/dc.rights.uri
Keywordrenal transplantationdc.subject
KeywordCYP3A5dc.subject
KeywordCYP3A4*22dc.subject
KeywordABCB1dc.subject
Keywordtherapeutic drug monitoringdc.subject
KeywordCYP3A5 GENOTYPEdc.subject
KeywordDOSE REQUIREMENTSdc.subject
KeywordACUTE REJECTIONdc.subject
KeywordVARIANT ALLELEdc.subject
KeywordRECIPIENTSdc.subject
KeywordDONORdc.subject
KeywordPOLYMORPHISMSdc.subject
Dewey Decimal GroupDDC 570 / Life sciencesdc.subject.ddc
LCSHPharmacogeneticsdc.subject.lcsh
LCSHDrug monitoringdc.subject.lcsh
LCSHRiskdc.subject.lcsh
MeSHKidney Transplantationdc.subject.mesh
MeSHCytochrome P-450 CYP3Adc.subject.mesh
MeSHDelayed Graft Functiondc.subject.mesh
TitleThe impact of CYP3A4*22 on tacrolimus pharmacokinetics and outcome in clinical practice at a single kidney transplant centerdc.title
Resource typeWissenschaftlicher Artikeldc.type
SWORD Date2020-01-28T13:25:48Zdc.date.updated
VersionpublishedVersiondc.description.version
DOIhttp://dx.doi.org/10.18725/OPARU-37996dc.identifier.doi
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-38058-4dc.identifier.urn
GNDPolymorphismusdc.subject.gnd
GNDTacrolimusdc.subject.gnd
GNDPharmakogenetikdc.subject.gnd
InstitutionUKU. Institut für Naturheilkunde und Klinische Pharmakologieuulm.affiliationSpecific
Peer reviewjauulm.peerReview
DCMI TypeCollectionuulm.typeDCMI
CategoryPublikationenuulm.category
In cooperation withSouth Valley University, Qena, Egyptuulm.cooperation
In cooperation withEberhard Karls Universität Tübingenuulm.cooperation
In cooperation withDr. Margarete Fischer-Bosch - Institut für Klinische Pharmakologie Stuttgartuulm.cooperation
In cooperation withKlinikum Stuttgartuulm.cooperation
DOI of original publication10.3389/fgene.2019.00871dc.relation1.doi
Source - Title of sourceFrontiers in Geneticssource.title
Source - Place of publicationFrontiers Mediasource.publisher
Source - Volume10source.volume
Source - Year2019source.year
Source - Article number871source.articleNumber
Source - eISSN1664-8021source.identifier.eissn
FundingU-PGx / Ubiquitous Pharmacogenomics (U-PGx): Making actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen / EC / H2020 / 668353uulm.funding
FundingRobert Bosch Stiftunguulm.funding
Open AccessDOAJ Golduulm.OA
Bibliographyuulmuulm.bibliographie
xmlui.metadata.dc.relation.isSupplementedByhttps://www.frontiersin.org/articles/10.3389/fgene.2019.00871/full#supplementary-materialdc.relation.isSupplementedBy


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