title: Monitoring the Intracellular Tacrolimus Concentration in Kidney Transplant Recipients with Stable Graft Function.
abstract: Although monitoring the intracellular concentration of immunosuppressive agents may be a promising approach to individualizing the therapy after organ transplantation, additional studies on this issue are needed prior to its clinical approval. We investigated the relationship between intracellular and whole blood concentrations of tacrolimus (IC-TAC and WB-TAC, respectively), the factors affecting this relationship, and the risk of rejection based upon IC-TAC in stable kidney recipients. Both IC-TAC and WB-TAC were measured simultaneously in 213 kidney recipients with stable graft function using LC-MS/MS. The tacrolimus ratio was defined as IC-TAC per WB-TAC. The genetic polymorphism of ABCB1 gene and flow cytometric analyses were conducted to probe the correlation between tacrolimus concentrations and the immunoreactivity status as a potential risk of rejection, respectively. The correlation between IC-TAC and WB-TAC was relatively linear (r = 0.67; P<0.001). The factors affecting the tacrolimus ratio were sex, hematocrit, and the transplant duration, as follows: a high tacrolimus ratio was noted in female patients, patients with a low hematocrit, and patients with a short transplant period. However, the tacrolimus ratio did not reflect the prior clinical outcomes (e.g., rejection) or the genetic polymorphism of ABCB1. After stimulation with phorbol-12-myristate 13-acetate and ionomycin, the proportion of T cells producing interferon-gamma or interleukin-2 was higher in the low-IC-TAC group than in the high-IC-TAC group. Further studies are required to evaluate the value of the intracellular tacrolimus concentrations in several clinical settings, such as rejection, infection, and drug toxicity.
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seung Seok
authors.initials: SS
authors.lastname: Han
authors.affiliation: Kidney Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Min Chang
authors.initials: MC
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sang-Il
authors.initials: SI
authors.lastname: Min
authors.affiliation: Kidney Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jung Pyo
authors.initials: JP
authors.lastname: Lee
authors.affiliation: Kidney Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dong Ki
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.|Kidney Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D002853:Chromatography, Liquid; D005260:Female; D006085:Graft Survival / Q000502:physiology*; D006801:Humans; D042541:Intracellular Space / Q000737:chemistry* / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000235:genetics / Q000628:therapy; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic / Q000379:methods; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000032:analysis* / Q000097:blood; D053719:Tandem Mass Spectrometry; D014019:Tissue Donors; D066027:Transplant Recipients
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D016559:Tacrolimus