{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:31:52Z","timestamp":1786516312824,"version":"build-2736575974"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tacrolimus (TAC) exhibits high pharmacokinetic variability post-liver transplantation (LT). Traditional models overlook the metabolic chimerism between recipient (intestinal) and donor (hepatic) genotypes. We aimed to evaluate a combined donor\u2013recipient CYP3A functional allele count predicting TAC exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This retrospective study analyzed 1,350 TAC trough measurements from 99 LT recipients.\n                      <jats:italic>CYP3A4<\/jats:italic>\n                      and\n                      <jats:italic>CYP3A5<\/jats:italic>\n                      functional alleles were summed into a combined pair-level framework (0\u20138 alleles). The primary outcome was the log-transformed concentration-to-dose ratio (log-CDR). Linear mixed-effects models (LMM) accounted for repeated measurements, adjusting for clinical and pharmacological covariates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The combined CYP3A functional allele count was the strongest genetic predictor of TAC exposure. Using the most prevalent group (4 alleles) as reference in multivariable LMMs, dose-normalized exposure significantly decreased by 43% and 48% in pairs with 5 and 6 functional alleles, respectively (p &amp;lt; 0.001). This gene-dose relationship remained stable across ICU, ward, and outpatient phases. The combined metric captured 4.2% of baseline variance (marginal\n                      <jats:italic>R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      = 0.042), indicating that most TAC exposure variability is driven by non-genetic clinical factors. Nevertheless, this approach doubled the explanatory power achieved with recipient genotype alone and remained an independent predictor after adjustment for major time-varying clinical confounders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The combined donor\u2013recipient CYP3A functional allele count provides a biologically coherent, temporally stable metric of TAC metabolism. Outperforming single-genome models, it offers a stratification tool to guide early post-operative initial dose strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1879383","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:00:09Z","timestamp":1786514409000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined donor\u2013recipient CYP3A functional allele count as an independent predictor of tacrolimus pharmacokinetics after liver transplantation"],"prefix":"10.3389","volume":"17","author":[{"given":"Luis","family":"Ramudo-Cela","sequence":"first","affiliation":[{"name":"Department of Hospital Pharmacy, Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas","place":["A Coru\u00f1a, Spain"]},{"name":"Hospital Pharmacy Research Group, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, University of A Coru\u00f1a (UDC)","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brais","family":"Mu\u00f1iz-Castro","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Information Technologies, University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]},{"name":"Research Center in Information and Communication Technologies (CITIC), University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Su\u00e1rez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Liver Transplantation, Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Otero-Ferreiro","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Liver Transplantation, Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilberto","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Information Technologies, University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]},{"name":"Research Center in Information and Communication Technologies (CITIC), University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Information Technologies, University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]},{"name":"Research Center in Information and Communication Technologies (CITIC), University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Cabalar","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Information Technologies, University of A Coru\u00f1a","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Margusino-Frami\u00f1\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Hospital Pharmacy, Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas","place":["A Coru\u00f1a, Spain"]},{"name":"Hospital Pharmacy Research Group, Instituto de Investigaci\u00f3n Biom\u00e9dica de A Coru\u00f1a (INIBIC), Complexo Hospitalario Universitario de A Coru\u00f1a (CHUAC), Sergas, University of A Coru\u00f1a (UDC)","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1186\/s43094-024-00731-0","article-title":"Studying the association between single nucleotide polymorphisms of metabolizing enzymes and the therapeutic serum levels of calcineurin inhibitors in Egyptian liver transplant patients","volume":"10","author":"Abuelsoud","year":"2024","journal-title":"Future J. 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