title: Tacrolimus Metabolite M-III May Have Nephrotoxic and Myelotoxic Effects and Increase the Incidence of Infections in Kidney Transplant Recipients.
abstract: BACKGROUND
  Tacrolimus (Tac) is one of the most commonly used immunosuppressive drugs after solid organ transplantation. Eight Tac metabolites have been described, but their clinical importance remains unclear. The aim of this study was quantification of the 2 major Tac metabolites, 13-O-demethyl (M-I) and 15-O-demethyl (M-III), in kidney transplant recipients and to link them with parameters of kidney and liver function, peripheral blood cell counts, and infection incidence.
  
  
  METHODS
  In 81 kidney transplant recipients, concentrations of Tac, M-I, and M-III were measured with the use of liquid chromatography combined with tandem mass spectrometry (LC-MS-MS).
  
  
  RESULTS
  There was a negative correlation between M-III levels and estimated glomerular filtration rate (eGFR; r = -0.244; P < .05). Also, a negative correlation between M-III concentrations and red blood cell count (RBC) was found (r = -0.349; P < .05). Neither concentrations of Tac nor of M-I correlated with eGFR or RBC. M-I, M-III, and Tac were not related to alanine aminotransferase activity. Significantly higher Tac and M-III concentrations in the group with all types of infections in comparison with the group without infections were observed (6.95 ± 2.09 ng/mL vs 5.73 ± 2.43 ng/mL [P = .03] and 0.27 ± 0.17 ng/mL vs 0.20 ± 0.11 ng/mL [P = .04], respectively).
  
  
  CONCLUSIONS
  The results suggest that higher concentrations of M-III may have a nephrotoxic or myelotoxic effect and result in higher incidence of infections. Further studies are needed to confirm if monitoring of M-III could minimalize adverse effects such as nephrotoxicity or infections.
authors: Transplantation Institute, Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
authors: J
authors: J
authors: Zegarska
authors: Department of Clinical Nursing, Medical University of Warsaw, Warsaw, Poland.
authors: E
authors: E
authors: Hryniewiecka
authors: Transplantation Institute, Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland.
authors: D
authors: D
authors: Zochowska
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: E
authors: E
authors: Samborowska
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: R
authors: R
authors: Jazwiec
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: A
authors: A
authors: Borowiec
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
authors: W
authors: W
authors: Tszyrsznic
authors: Transplantation Institute, Department of General and Transplantation Surgery, Medical University of Warsaw, Warsaw, Poland.
authors: A
authors: A
authors: Chmura
authors: Department of General, Vascular, and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland.
authors: S
authors: S
authors: Nazarewski
authors: Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland; Department of Biology, University of Warsaw, Warsaw, Poland.
authors: M
authors: M
authors: Dadlez
authors: Transplantation Institute, Department of Immunology, Transplant Medicine, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland. Electronic address: leszek.paczek@wum.edu.pl.
authors: L
authors: L
authors: Paczek
mesh_terms: D000328:Adult; D002853:Chromatography, Liquid; D004394:Dydrogesterone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism*; D015994:Incidence; D007239:Infections / Q000453:epidemiology*; D007668:Kidney / Q000187:drug effects; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000009:adverse effects* / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D066027:Transplant Recipients
chemical_list: D007166:Immunosuppressive Agents; C037589:21-hydroxy-9beta,10alpha-pregna-5,7-diene-3-ol-20-one; D004394:Dydrogesterone; D016559:Tacrolimus