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.

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.