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a Author for correspondence. Fax 49-551-398551; e-mail ewieland{at}med.uni-goettingen.de
Background: The acyl glucuronide (AcMPAG) of mycophenolic acid (MPA) has been found to possess pharmacologic and potentially proinflammatory activity in vitro. To establish its pharmacologic and toxicologic relevance in vivo, a reversed-phase HPLC method was modified to simultaneously determine MPA, the phenolic MPA-glucuronide (7-O-MPAG), and AcMPAG. In addition, cross-reactivity of AcMPAG in the Emit assay for MPA was investigated.
Methods: The procedure used simple sample preparation, separation with a Zorbax Eclipse-XDB-C8 column, and gradient elution. AcMPAG was quantified as 7-O-MPAG-equivalents.
Results: The assay was linear up to 50 mg/L for MPA, 250 mg/L for
7-O-MPAG, and 10 mg/L for AcMPAG (r >0.999). Detection
limits were 0.01, 0.03, and 0.04 mg/L for MPA, 7-O-MPAG, and AcMPAG,
respectively. The recoveries were 99–103% for MPA, 95–103% for
7-O-MPAG, and 104–107% for AcMPAG. The within-day imprecision was
<5.0% for MPA (0.2–25 mg/L), <4.4% for 7-O-MPAG (10–250 mg/L),
and 
14% for AcMPAG (0.1–5 mg/L). The between-day
imprecision was <6.2%, <4.5%, and 14% for MPA, 7-O-MPAG, and
AcMPAG, respectively. When isolated from microsomes, purified AcMPAG
(1–10 mg/L) revealed a concentration-dependent cross-reactivity in an
Emit assay for the determination of MPA ranging from 135% to 185%.
This is in accordance with the bias between HPLC and Emit calculated in
270 samples from kidney transplant recipients receiving mycophenolate
mofetil therapy, which was greater (median, 151.2%) than the
respective AcMPAG concentrations determined by HPLC. AcMPAG was found
to undergo hydrolysis when samples were stored up to 24 h at room
temperature or up to 30 days at 4 °C or -20 °C. Acidified
samples (pH 2.5) were stable up to 30 days at -20 °C.
Conclusions: The HPLC and Emit methods for AcMPAG described here may allow investigation of its relevance for the immunosuppression and side effects associated with mycophenolate mofetil therapy.
The following articles in journals at HighWire Press have cited this article:
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