Mycophenolic Acid Metabolites Acyl-Glucuronide and Glucoside Affect the Occurrence of Infectious Complications and Bone Marrow Dysfunction in Liver Transplant Recipients

Abstract

BACKGROUND Mycophenolic acid (MPA) prodrugs are anti-proliferative immunosuppressive agents commonly used after organ transplantation. Although they are generally well tolerated by patients, adverse effects may occur. It is postulated that MPA metabolites could also contribute to these adverse effects. MATERIAL AND METHODS The objective of this study was the assessment of concentrations of total MPA and its metabolites, phenyl glucuronide (MPAG), acyl glucuronide (AcMPAG) and glucoside (GluMPA), using liquid chromatography combined with mass spectrometry (LC/MS/MS) in two groups: kidney transplant recipients and liver transplant patients. Associations of MPA and its metabolites with adverse effects were analyzed. RESULTS The study group consisted of 211 recipients of liver or kidney transplants who received immunosuppressive therapy, including MPA prodrugs. Multivariant analysis showed a positive influence of MPA on gastroenterotoxicity in kidney transplant recipients. In liver patients, gastroenterotoxicity was associated with lower MPAG concentrations. A positive influence of AcMPAG on bacterial infections in liver transplant patients was observed. In liver transplant recipients, a positive influence of MPA and a negative influence of GluMPA levels on the PLT count were revealed. MPA and its metabolites did not influence the hemoglobin levels in both groups. There were no significant relationships among MPA, its metabolites and WBC counts. CONCLUSIONS In kidney transplant recipients, total MPA trough concentration is associated with gastroenterotoxicity and its monitoring could have important role in management of gastrointestinal complications. The quantification of AcMPAG in liver recipients receiving MPA may be helpful in avoiding bacterial infections. GluMPA seems to have a toxic effect on thrombopoiesis.

Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

“…The equations for MPA, MPAG and AcMPAG were y = 6.0395 x + 0.1258, y = 3.0525 x + 0.0559 and y = 4.0896 x + 0.0127, respectively. To our knowledge, in comparison with other published methods that have simultaneously quantified MPA, MPAG, and AcMPAG (Benoit‐Biancamano et al, ; Delavenne et al, ; Figurski et al, ; Iboshi et al, ; Kawanishi et al, ; Klepacki et al, ; Zegarska et al, ; Zhang et al, ), no other assays have obtained better sensitivity for MPA and MPAG. On the other hand, only Figurski et al () reported a lower LLOQ (0.0002 μg/mL) for free AcMPAG concentration in plasma compared with 0.00467 μg/mL obtained in our assay.…”

“…We have developed a sensitive LC–MS/MS assay for the simultaneous quantification of MPA, MPAG and AcMPAG in HepaRG cell culture medium, using MPA‐d 3 and MPAG‐d 3 as internal standards. LC–MS/MS assays for MPA and/or metabolites have been described in human plasma (Delavenne, Juthier, Pons, Mariat, & Basset, ; Figurski, Korecka, Fields, Waligorska, & Shaw, ; Kawanishi et al, ; Zegarska et al, ; Zhang, Chow, & Renbarger, ), urine (Benoit‐Biancamano et al, ; Klepacki et al, ), dried blood spots (Iboshi et al, ) and human liver microsomes (Mohamed, Harvey, & Frye, ). In contrast to other biological fluids (i.e.…”

“…In contrast to the frequently used ESI for the quantification of MPA and metabolites (Benoit‐Biancamano et al, ; Delavenne et al, ; Figurski et al, ; Iboshi et al, ; Kawanishi et al, ; Klepacki et al, ; Zegarska et al, ; Zhang et al, ), a DUIS approach combining both ESI and APCI ionizations was utilized in our assay. The ESI probe and the APCI corona needle are positioned in a 90° angle in the ion source and have distinctive ionization zones.…”

Mycophenolate mofetil‐related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs

“…Others have studied the metabolite AcMPAG as a potential mediator of adverse side effects for patients prescribed MMF both in vitro and in vivo and suggest there may be a relationship between AcMPAG and gastrointestinal side effects; however, AcMPAG has not been convincingly shown to be a mediator of leukopenia. In a study by van Agteren et al, they did not find a difference in AcMPAG concentrations in 332 kidney transplant patients that experienced leukopenia compared to those that did not .…”

Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients

“…Recently, Zegarska et al have been reported that AcMPAG concentrations in liver transplant recipients is related to the development of bacterial infection (8). In addition, Yoshimura et al have been reported that the cutoff values of AcMPAG AUC0-24 for successful gastrointestinal acute graft-versushost disease prevention in hematopoietic stem cell transplant patients were 15.6 μg•hr/mL (9).…”