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However, &gt;99% of tacrolimus measured in WB is bound to erythrocytes and plasma proteins, which are the pharmacologically inactive fractions. The pharmacologically active fractions, the free (or unbound) tacrolimus in plasma and the intracellular tacrolimus, make up 1% or less of the WB concentration. The mechanism of action of tacrolimus is to inhibit the enzyme calcineurin within T lymphocytes and, therefore, measuring the intralymphocytic tacrolimus concentration may better reflect its pharmacodynamic effects and better correlate with clinical outcomes. However, studies on intracellular tacrolimus concentrations have shown conflicting results. In this review, we argue that we need to overcome the analytical limitations of current assays for the measurement of intracellular tacrolimus before moving this technique into the clinical setting. The validity and standardization of the cell isolation process before the measurement of the intracellular tacrolimus concentration is as important as the measurement itself but has received little attention in our view. Recent evidence suggests that the addition of an inhibitor of P\u2010glycoprotein, an efflux transporter expressed on lymphocytes, prevents the expulsion of tacrolimus during the cell isolation process. Refining the technique for the intracellular tacrolimus concentration measurement should be the focus followed by clinical evaluation of its association with rejection risk.<\/jats:p>","DOI":"10.1111\/bcp.15946","type":"journal-article","created":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T01:30:10Z","timestamp":1698456610000},"page":"1530-1541","source":"Crossref","is-referenced-by-count":17,"title":["Should we abandon therapeutic drug monitoring of tacrolimus in whole blood and move to intracellular concentration measurements?"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4087-9032","authenticated-orcid":false,"given":"Suwasin","family":"Udomkarnjananun","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Faculty of Medicine Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society  Bangkok Thailand"},{"name":"Excellence Center for Organ Transplantation (ECOT) King Chulalongkorn Memorial Hospital, Thai Red Cross Society  Bangkok Thailand"},{"name":"Renal Immunology and Transplantation Research Unit, Faculty of Medicine Chulalongkorn University  Bangkok Thailand"},{"name":"Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology Chulalongkorn University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanee","family":"Eiamsitrakoon","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Faculty of Medicine Thammasat University  Pathum Thani Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda C. 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