Elsevier

Transplantation Proceedings

Volume 50, Issue 7, September 2018, Pages 2235-2239
Transplantation Proceedings

13th Congress of the Polish Transplantation Society: Part II
Experimental transplantation
Evaluation of the Relationship Between Concentrations of Tacrolimus Metabolites, 13-O-Demethyl Tacrolimus and 15-O-Demethyl Tacrolimus, and Clinical and Biochemical Parameters in Kidney Transplant Recipients

https://doi.org/10.1016/j.transproceed.2018.03.025Get rights and content

Highlights

  • We observed higher tacrolimus (Tac) levels in patients with hypercholesterolemia.

  • Higher tacrolimus concentrations were observed in patients with hypertriglyceridemia.

  • There was a positive correlation between 13-O-demethyl Tac/Tac and ALAT.

  • We found a negative correlation between 13-O-demethyl Tac/Tac and hemoglobin.

  • 13-O-demethyl Tac/Tac may be a marker of myelotoxicity and hepatotoxicity.

Abstract

Background

Tacrolimus (Tac), an essential component of immunosuppressive therapy after solid-organ transplantation, has a narrow therapeutic index and requires therapeutic drug monitoring. Monitoring of Tac predose blood concentrations seems to be not always sufficient to avoid adverse effects. The aim of the study was to evaluate the levels of main Tac metabolites, 13-O-demethyl tacrolimus (13-DMT), 31-O-demethyl tacrolimus (31-DMT), and 15-O-demethyl tacrolimus (15-DMT), in kidney transplant recipients and to link them to clinical and biochemical parameters.

Methods

In 63 kidney transplant patients, concentrations of 13-DMT, 31-DMT, and 15-DMT were quantified using liquid chromatography combined with tandem mass spectrometry (LC/MS/MS).

Results

None of the patients had detectable 31-DMT blood levels. There was a positive correlation between 13-DMT/Tac and alanine aminotransferase (ALAT) (r = 0.29, P = .046) and a negative correlation between 13-DMT/Tac and hemoglobin (r = −0.33, P = .008). Tac level did not correlate with ALAT nor with hemoglobin. There was no relationship between 13-DMT/Tac or 15-DMT/Tac and other biochemical or hematologic parameters or data, such as age, body mass index, arterial pressure, or time posttransplant. We observed significantly higher Tac concentrations in patients with hypercholesterolemia or hypertriglyceridemia compared with those without these comorbidities (6.45 ± 2.32 vs 5.16 ± 2.12 ng/mL, P = .043; 6.60 ± 2.30 vs 5.34 ± 2.20 ng/mL, P = .033, respectively).

Conclusion

Our data may reflect 13-DMT accumulation in liver dysfunction and higher Tac clearance in anemia. However, these results may suggest that 13-DMT/Tac ratio is a marker of myelotoxicity and hepatotoxicity. Further studies should be carried out to determine whether monitoring of 13-DMT could be beneficial in minimizing the adverse effects.

Section snippets

Materials and Methods

Blood samples were obtained from patients who gave their written informed consent to participate in the study. Sixty-three stable patients who underwent kidney transplantation were included in the study. Their median age was 51.3 (range, 22–73) years. The study group included 36 male and 27 female subjects. The median posttransplant time was 36.1 (range, 1–209) months. Trough blood samples of 2 mL were collected during routine outpatient visits into ethylene-diamine tetraacetic acid

Results

Patients' demographics and concentrations of Tac and its metabolites are shown in Table 1. None of the patients had detectable 31-DMT blood levels. There was a positive correlation between 13-DMT/Tac and ALAT (r = 0.29, P = .046) (Fig 1) and a similar relationship between 13-DMT and ALAT (r = 0.41, P = .004). We also found a negative correlation between 13-DMT/Tac and hemoglobin (r = −0.33, P = .008) (Fig 1). A similar relationship was observed between Tac dose per kilogram body weight and

Discussion

In this study we have evaluated the concentrations of Tac and its main metabolites using LC/MS/MS in kidney transplant recipients. There have been some previous reports on quantification of Tac metabolites using the same method [5], [9], [10], but data on the clinical importance of these metabolites are limited.

We observed a positive correlation between 13-DMT/Tac and ALAT. This could be explained by the fact that liver dysfunction leads to accumulation of Tac and its metabolites. Over 95% of

Conclusion

Our data show that 13-DMT/Tac ratio is significantly associated with liver function and complete blood count parameters. The clinical significance of these findings is unclear, but may reflect changes in the metabolism of the drug under special conditions, 13-DMT accumulation during liver dysfunction, and higher Tac clearance in the case of anemia. However, the findings could also suggest that the 13-DMT/Tac ratio is a marker of myelotoxicity and hepatotoxicity. In this case, quantification of

Acknowledgments

The authors thank Astellas Pharma for kindly donating standards of tacrolimus metabolites.

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This study was supported by grants from the Polish National Center of Research and Development (NR13014410) and the Polish National Science Centre (2013/09/B/NZ2/00275).

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