Significant Correlations between p-Cresol Sulfate and Mycophenolic Acid Plasma Concentrations in Adult Kidney Transplant Recipients

Liquid Chromatography-Mass Spectrometry Analytical Methods for the Quantitation of p-Cresol Sulfate and Indoxyl Sulfate in Human Matrices: Biological Applications and Diagnostic Potentials

“…The difference in the associations between the two calcineurin inhibitors might be attributed, according to the authors, to differences in their plasma protein binding properties [93]; however, additional pharmacokinetic interacting mechanisms may also be possible. From the literature, Rong et al [124] reported a positive correlation between plasma pCS and mycophenolic acid trough concentrations [124], but this study did not find an association with tacrolimus. More studies are needed to characterize the interactions between immunosuppressants and IxS or pCS, which can potentially cause clinically significant pharmacodynamic effects in this already fragile population [124][125][126].…”

“…From the literature, Rong et al [124] reported a positive correlation between plasma pCS and mycophenolic acid trough concentrations [124], but this study did not find an association with tacrolimus. More studies are needed to characterize the interactions between immunosuppressants and IxS or pCS, which can potentially cause clinically significant pharmacodynamic effects in this already fragile population [124][125][126].…”

Increased levels of a mycophenolic acid metabolite in patients with kidney failure negatively affect cardiomyocyte health

“…To verify that MPA-G is indeed the mediator found in the dialysate of patients with CKD negatively affecting cardiomyocytes, the overall metabolic activity and cell viability of HL-1 cells was assessed applying different concentrations of MPA-G. MPA-G was tested in the range of 100–500 µg/ml, covering the concentration range previously reported in a dialysis patient on regular dosing with mycophenolate mofetil (MMF) ( 16 )—the prodrug of MPA—as well as in patients on MMF with post-transplant acute kidney failure ( 17 ). In comparison, effects of the drug MPA were tested at 100–500 µg/ml, enabling a comparison with comparable MPA-G dosing, but also concentrations down to 0.01 µg/ml were tested, covering the lower range of MPA levels reported in patients with CKD on MMF treatment ( 16 – 18 ). Concentrations of 100–500 µg/ml MPA-G decreased the overall metabolic activity of cardiomyocytes in a dose-dependent way ( Figure 3A ).…”

“…Also, dialysis patients with a single dose of 1-g MMF showed a very slow clearance of MPA-G with an area under the curve (AUC) of 1,565 µg/ml h being five times as much as expected in subjects with normal kidney function ( 16 ). Within 12 months after kidney transplantation, patients revealed MPA-G levels of 2.8–84.3 µg/ml, with highest concentrations for lowest GFR values ( 18 ) and with high MPA-G levels up to 358 µg/ml detected in patients with post-transplant acute kidney failure ( 17 ). These concentrations are very close, respectively, within the range in which MPA-G adversely affected cardiomyocyte health in our assays (100–500 µg/ml).…”

“…For example, one study only found MPA-G but not MPA to accumulate in patients with post-transplant acute kidney failure treated daily with 3-g MMF, reporting MPA levels in the range of 0.5–2.3 µg/ml ( 17 ). Others reported maximal levels of MPA in the range of 5.1–16.0 μg/ml in hemodialysis patients 0.66 h after intake of 0.5–1 g MMF ( 16 ); concentrations within 0.2–10.4 µg/ml in patients up to 12 months after kidney transplantation ( 18 ), or even levels rising to ∼20–30 µg/ml in patients following solid organ transplant dosed 1–2 g MMF/day ( 25 ).…”