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a Author for correspondence. Fax 49-551-398551; e-mail ewieland{at}med.uni-goettingen.de
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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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.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although the latter has not yet been demonstrated for AcMPAG, the possibility exists that this acyl glucuronide contributes to side effects observed in patients receiving MMF therapy through the mechanisms mentioned above. Determination of AcMPAG plasma concentrations may therefore be of importance for the monitoring of MMF therapy with regard to its pharmacologic and toxicologic effects. To investigate these effects, appropriate analytic methods are needed. We have modified our recently published HPLC method for the simultaneous determination of MPA and 7-O-MPAG (10) to also monitor AcMPAG.
We found that AcMPAG cross-reacts with the MPA antibody used in the commercially available Emit assay (Dade-Behring). This could explain the 5–40% overestimation of Emit MPA values compared with HPLC in different transplant recipients (11)(12)(13). The overestimation was found to correlate with the AcMPAG plasma concentrations determined with a different HPLC procedure (14). Establishing the extent of the cross-reactivity of AcMPAG in the Emit assay for MPA is therefore a prerequisite for the interpretation of Emit test results with respect to the monitoring of MMF therapy.
Acyl glucuronides are known to readily undergo hydrolysis to the parent drug under neutral or slightly alkaline conditions, with the rate of hydrolysis being dependent on the temperature (8)(9)(15). Furthermore, they can accumulate in the blood of patients with renal failure, and in vitro hydrolysis in plasma samples obtained from such patients could compromise the quantification of both the metabolite and the parent compound. Therefore, we investigated the stability of AcMPAG in patient plasma samples. To improve the accuracy of the analysis, we evaluated the possibility of stabilizing samples according to the procedure recommended by Hyneck et al. (15) for tolmetin acyl glucuronide.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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sample preparation
The sample pretreatment procedure was as described previously
(10). Briefly, 200 µL of plasma and 100 µL of
acetonitrile containing the internal standard MPAC (15 mg/L) were mixed
by vortex-mixing in a 1.5-mL polypropylene tube for 5 s. This was
followed by the sequential addition of 20 µL of 250 g/L sodium
tungstate and 20 µL of 150 g/L perchloric acid and vortex-mixing for
15 s after each addition. The sample was then centrifuged for 5
min at 10 000g, and 50 µL of the supernatant was removed
for chromatography.
chromatographic conditions
To determine AcMPAG plasma concentrations simultaneously with MPA
and 7-O-MPAG concentrations in one HPLC run with favorable performance
characteristics for all three analytes, we modified the chromatographic
conditions used previously (10). The separation was achieved
with a Zorbax Eclipse XDB-C8 column (25 cm x 4.6 mm i.d.;
particle size, 5 µm; Hewlett Packard) as stationary phase. This
column is able to separate highly polar compounds such as MPA and
glucuronide metabolites, and is also stable over the wide pH range
required for the method presented here. The mobile phase (flow rate,
1.2 mL/min) consisted of solution A (250 mL acetonitrile and 750 mL
phosphate buffer, pH 3.0, 20 mmol/L final concentration) and solution B
(700 mL acetonitrile and 300 mL phosphate buffer, pH 6.5, 20 mmol/L
final concentration) that formed the following gradient: 0–4.5 min
(7% B); 4.5–7 min (34% B); 7–13.5 min (34% B); 13.5–14 min (100%
B); 14–17.5 min (100% B); 17.5–18 min (7% B). The column was
maintained at 42 °C. The HPLC system consisted of a chromatographic
pump (M480), an automatic injector (GINA 50), a diode array detector
(UVD 340S), and a computer interface system controller linked to a PC
(Dionex-Gynkotek). The compounds were quantified by absorbance at 215
nm in internal standard mode, using peak-area ratios. The Chromeleon
software (Dionex-Gynkotek), Ver. 5.42, was used for recording and
calculating the data and also for recording the UV spectra when
required. The calibration and quality control were performed by use of
solutions prepared in-house (10), which were analyzed with
each run.
assessment of performance characteristics
The detection limit of the method was calculated using a
signal-to-noise ratio of 3. For this purpose, the noise signal of the
baseline was obtained from a segment of the chromatogram that preceded
the AcMPAG, MPA, or 7-O-MPAG peak. The limit of quantification was
defined according to Shah et al. (16) as the smallest
concentration of AcMPAG with a between-day imprecision <20%
and a mean inaccuracy <20%. The linearity of the method was
established using drug-free plasma with MPA, 7-O-MPAG, and AcMPAG added
to yield concentrations of 0.04–50 mg/L for MPA, 1–500 mg/L for
7-O-MPAG, and 0.05–10 mg/L for AcMPAG. The within- and between-run
imprecision and extraction efficiency were studied by adding the
compounds to drug-free plasma; final concentrations were 0.2, 1, and 25
mg/L MPA; 10, 50, and 250 mg/L 7-O-MPAG; and 0.1, 1 and 5 mg/L
AcMPAG.
The extraction efficiency was calculated by comparing peak areas obtained from the extracted plasma samples with MPA, AcMPAG, or 7-O-MPAG added with the peak areas obtained for acetonitrile-water (80:20, by volume) solutions containing the same amount of the compounds, which were injected directly onto the column without extraction. To obtain information on the accuracy of the method, the analytical recovery was determined by adding known amounts of MPA (0.2, 1, and 25 mg/L), 7-O-MPAG (10, 50, and 250 mg/L), and AcMPAG (0.1, 1, and 5 mg/L) to a drug-free plasma pool. The recovery was calculated by comparing the measured concentrations with the expected concentrations.
Potential chromatographic interference by commonly administered drugs was evaluated by analysis of patient specimens received for routine therapeutic drug monitoring, including transplant patients receiving immunosuppressive therapy without MMF, therapeutic drug monitoring quality-control sera (Chiron Diagnostics), and drug standards dissolved in methanol. In addition, the existence of endogenous chromatographic interferences was evaluated by separate analysis of 50 patient specimens free of MPA.
method comparison
Fifty-one plasma specimens derived from pharmacokinetic studies in
renal, liver, or heart transplant recipients were used to compare the
method presented here with the established HPLC procedure published
previously (10) with respect to MPA and 7-O-MPAG plasma
concentrations.
estimation of AcMPAG CROSS-REACTIVITY WITH THE EMIT MPA
ANTIBODY
The AcMPAG cross-reactivity in the Emit assay was studied with
drug-free plasma to which AcMPAG was added to yield final
concentrations of 1.25, 2.5, 5, and 10 mg/L. Each solution was divided
into two 450-µL portions. To the first portion, 45 µL of NaOH (2
mol/L) was added, and the samples were then left at room temperature
for 2 h to achieve complete hydrolysis of AcMPAG to MPA. The pH
was then adjusted to 7.4 by the addition of
H3PO4 (850 g/L), and the
samples were analyzed with the Emit. To verify complete hydrolysis of
AcMPAG, an aliquot of each sample was subjected to HPLC analysis. The
second portion (450 µL) served as control and was analyzed directly
by Emit or HPLC after the volume was corrected using doubly distilled
water. To investigate whether the immunologic reactivity was affected
by the pH changes during the hydrolysis procedure, the same protocol
was applied to solutions to which matching MPA concentrations instead
of AcMPAG had been added. All experiments were performed in duplicate
and repeated on another day.
To examine the effect of MPA on the cross-reactivity of the metabolite AcMPAG in the immunoassay, plasma samples (n = 2) containing either 2.5 or 5 mg/L AcMPAG were supplemented with 1 and 5 mg/L MPA, respectively, and treated according to the protocol above. In addition, 270 samples collected from kidney transplant recipients receiving MMF therapy were investigated in parallel, using HPLC and Emit, and the absolute differences in the results from both techniques were compared to the respective AcMPAG concentrations determined by HPLC.
stability of AcMPAG IN HUMAN PLASMA AS DETERMINED BY
HPLC
To investigate the stability of AcMPAG, two plasma pools from
patients receiving MMF therapy as well as two drug-free plasma pools
supplemented with AcMPAG were used. These pools contained between 0.7
and 4.09 mg/L AcMPAG. An aliquot from each pool was acidified using
phosphoric acid (850 g/L) to pH 2.5. The resulting pools were divided
into 200-µL aliquots, which were split into three parts and stored
separately at -20 °C, 4 °C, or room temperature. AcMPAG
concentrations were determined immediately after preparation of the
pools and after 1 day, 7 days, and 30 days of storage for the samples
kept at -20 °C and 4 °C. Samples stored at room temperature were
analyzed immediately after preparation of the pools and after 1, 2, 5,
12, and 24 h of storage.
statistics
The nonparametric regression procedure of Passing and Bablok
(17) was used for method comparison (EVAPAK, Ver. 2.08;
Boehringer Mannheim). For correlation analysis, Spearman correlation
coefficient was calculated. To establish the stability of AcMPAG,
critical differences (dk) were
calculated according to the formula dk
= 2 x 
x S, with S
being the standard deviation of the method from day to day. Values were
considered significantly different if the absolute difference between
two values, x1 and
x2, was greater than
dk
(|x1 -
x2| >
dk) (18).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B, respectively. The retention times of 7-O-MPAG,
AcMPAG, MPAC, and MPA were 4.2, 7.8, 12.5, and 13.4 min, respectively.
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No interferences were observed from endogenous compounds and various drugs that are potentially coadministered with MMF, such as acetaminophen, amikacin, amoxicillin, amphotericin B, caffeine, carbamazepine, cefazolin, chloramphenicol, cimetidine, clemastine, clonazepam, cyclosporin A, diazepam, digoxin, dopamine, gentamicin, lidocaine, netilmicin, phenobarbital, phenytoin, prednisolone, prednisone, primidone, rapamycin, salicylate, tacrolimus, theophylline, tobramycin, and vancomycin.
Linearity was verified up to 50 mg/L for MPA, up to 250 mg/L for 7-O-MPAG, and up to 10 mg/L for AcMPAG (correlation coefficients, r >0.999).
The within- and between-run imprecision and the analytical recovery for
AcMPAG are given in Table 1
. For AcMPAG, the detection limit was 0.04 mg/L, the lower limit
of quantification was 0.1 mg/L, and the extraction efficiency was
72–78% (n = 3) in the working range (0.1–5 mg/L). Because the
sample pretreatment procedure was the same as that published previously
(10), the performance characteristics for MPA and 7-O-MPAG
remained similar. In the working range for MPA (0.2–25 mg/L), the
within-run imprecision was 2.0–5.0% (n = 10), the between-run
imprecision was 3.4–6.2% (n = 10), the analytical recovery was
99–103% (n = 5), and the extraction efficiency was 56–60%
(n = 3). In the working range for 7-O-MPAG (10–250 mg/L), the
within-run imprecision was 2.3–4.4% (n = 10), the between-run
imprecision was 3.6–4.5% (n = 10), the analytical recovery was
95–103% (n = 5), and the extraction efficiency was 73–78%
(n = 3). The detection limits (signal-to-noise ratio = 3)
were 0.01 mg/L for MPA and 0.03 mg/L for 7-O-MPAG.
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The procedure requires 10 min for a single sample preparation, 30 min for preparation of a batch of 20 samples, and 21 min for a single chromatographic development.
Excellent agreement was observed between plasma MPA (r
= 0.998; y = 1.019 (0.998–1.045)x -
0.006 (-0.065 to 0.099); 68% median distance = 0.159;
Sy|x = 0.26; n = 51) and 7-O-MPAG
(r = 0.998; y = 1.031
(1.0–1.063)x + 0.313 (-1.37 to 1.0); 68% median
distance = 2.51; Sy|x = 2.69; n = 51)
concentrations determined by the new (y) and the original
procedure (x; Fig. 2
)
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In 406 patient samples obtained during pharmacokinetic investigations, AcMPAG concentrations were 0.05–5.4 mg/L with a median of 0.75 mg/L.
cross-reactivity of AcMPAG IN EMIT ASSAY
As shown in Table 2
, values obtained with the Emit assay in plasma samples
supplemented with AcMPAG were 135.3–184.8% higher when
compared with values observed with the same samples after hydrolysis of
AcMPAG to MPA using NaOH. Furthermore, the cross-reactivity of AcMPAG
showed a concentration-dependent increase in the Emit. The completeness
of hydrolysis was verified by HPLC. The hydrolysis procedure itself had
no influence on the immune reaction as shown with control experiments
in which AcMPAG was replaced by MPA (Table 2
).
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MPA, when added to two plasma pools containing either 2.5 or 5 mg/L AcMPAG, did not influence the cross-reactivity of AcMPAG in the Emit assay. After the addition of 1 mg/L MPA to these pools, mean cross-reactivities of 149.3% and 165.9% were observed (n = 2). With 5 mg/L MPA, the cross-reactivities were 154.4% and 166.0%, respectively (n = 2).
Correlation analysis (Fig. 3
) between AcMPAG concentrations measured by HPLC and the bias
between MPA concentrations determined by Emit and HPLC
(MPAEmit - MPAHPLC) in 270
patients samples revealed an r of 0.88. The interassay bias
was in general higher than would be expected from AcMPAG concentrations
determined with HPLC (median, 151.2%; 16–84 percentile,
98.5–278.6%). This is in accordance with an increased immunologic
cross-reactivity of AcMPAG in the Emit assay as shown above.
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stability of AcMPAG IN PLASMA SAMPLES
Storage of plasma pools containing AcMPAG at concentrations
observed in vivo at room temperature produced a significant
time-dependent decrease in the concentration of this metabolite (Fig. 4
A). Compared with initial values (median, 2.61 mg/L; range,
0.7–4.09 mg/L; n = 4), there was a median AcMPAG decrease of
37.8% (range, 35.9–44.3%; n = 4) after 24 h, producing
concentrations between 0.39 and 2.62 mg/L (median, 1.62 mg/L). This
decrease was not observed when the plasma pools were adjusted to pH 2.5
before storage (Fig. 4A
). When nonacidified samples were stored at
4 °C, there was a significant decrease of AcMPAG, with median
concentrations of 1.83 mg/L (range, 0.41–3.43 mg/L; n = 4) on day
1, 1.61 mg/L (range, 0.32–3.13 mg/L; n = 4) on day 7, and 1.01
mg/L (range, 0.23–1.88 mg/L; n = 4) on day 30. This decrease
corresponds to a 29.7% median loss of AcMPAG within 1 day (range,
16.1–41.9%; n = 4), 38.4% (range, 23.0–53.9%; n = 4)
within 7 days, and 61.4% (range, 54–73.3%; n = 4) within 30
days (Fig. 4B
). When nonacidified samples were stored at -20 °C for
7 or 30 days, significant decreases of AcMPAG to median concentrations
of 2.30 mg/L (range, 0.6–3.79 mg/L; n = 4) on day 7 and 2.06 mg/L
(range, 0.55–3.23 mg/L; n = 4) on day 30 were also observed (Fig. 4B
). When acidified samples were stored for >24 h at 4 °C, the
AcMPAG concentration was significantly reduced to a median
concentration of 2.30 mg/L (range, 0.59–3.77 mg/L; n = 4) on day
7, and a median concentration of 2.22 mg/L (range, 0.53–3.69 mg/L;
n = 4) on day 30 (Fig. 4B
). In contrast, the metabolite was stable
up to 30 days at -20 °C in all acidified samples. A nonsignificant
loss of AcMPAG was found up to 24 h in the acidified samples
stored at 4 °C as well as in the nonacidified samples stored at
-20 °C.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and the chemical
synthesis is difficult (8), it was quantified as
7-O-MPAG-equivalents. Because of the comparable extraction efficiencies
of AcMPAG and 7-O-MPAG and their similar UV spectra, a favorable
analytical recovery was obtained (Table 1
). When needed, the lower
quantification limit for AcMPAG of 0.1 mg/L (between-run imprecision,
14%) can be lowered to 0.05 mg/L by increasing the injection volume.
The linearity of the method described was sufficient for >95% of the
plasma samples investigated to date. The remaining samples had to be
injected either at a reduced volume because of MPAG concentrations
exceeding the capacity of the UV detector or at a higher volume because
of low AcMPAG concentrations. The low pH used during sample
pretreatment is favorable with respect to the stability of AcMPAG. This
allows analysis of large series, using an autosampler, because samples
can then be kept at room temperature for up to 24 h. More than 600
chromatographic runs can be achieved with one Eclipse XDB-C8 column
without any deterioration of the separation performance.
The method was validated by comparison with the original HPLC method
(10), which has been used in pharmacokinetic studies on MPA
in pediatric and adult renal transplant recipients
(19)(20). Very good agreement between the two
methods was observed for both MPA and 7-O-MPAG (Fig. 2
).
The method is also suitable for the determination of the free MPA fraction after ultrafiltration of the plasma using the protocol described in the original procedure (10) as well as for the determination of the prodrug MMF (retention time, ~9 min; data not shown). This may be of potential interest in patients receiving MMF through the intravenous route (1)(21).
As described previously by our group (11)(14),
the Emit MPA assay also reflects AcMPAG plasma concentrations because
of the cross-reactivity of its anti-MPA antibody with AcMPAG. In
contrast, 7-O-MPAG shows no cross-reactivity
(3)(13) in this assay, which suggests that the
epitope recognized by the anti-MPA antibody includes the free hydroxyl
group at position seven of the phenol ring of the molecule. Because
AcMPAG has pharmacologic activity in vitro (6), it can be
speculated that the Emit data may better reflect the immunosuppression
during MMF treatment than will values obtained with methods that
measure only MPA. However, the interpretation of values determined by
this technique is difficult, particularly because of the
concentration-dependent cross-reactivity (Table 2
). Such increased
cross-reactivity may be explained by the complementarity of the binding
site of an antibody to different antigens as well as by the flexibility
of the binding site to undergo conformational changes
(22)(23). This leads to binding of different
antigens, but with different affinities (in our case, higher for AcMPAG
than MPA). The presence of MPA in the samples did not attenuate the
cross-reactivity of AcMPAG with the Emit antibody. Furthermore,
interpretation of Emit test results must consider that AcMPAG, as a
metabolite of MPA, shows a different pharmacokinetic profile compared
with the parent drug and reaches its peak concentration
(cmax) 1–3 h after the
cmax of MPA (13).
Therefore, the impact of AcMPAG on the MPA concentration determined
with the Emit is relatively low during the first hour after MMF
administration but increases considerably 4–8 h post dose
(13). Fig. 1
shows a case in which AcMPAG reaches a
concentration (1.85 mg/L) comparable to that of MPA (1.25 mg/L) 6
h after the MMF dose. In addition, the interindividual variation in MPA
pharmacokinetics (1)(14) is also a factor that
influences the AcMPAG/MPA ratio, which should be kept in mind when
interpreting clinical data. Therefore, the role of Emit for the
monitoring of MPA therapy with respect to AcMPAG needs further
investigation with larger numbers of patients.
Another problem, which must be considered when analyzing biological specimens that contain acyl glucuronide conjugates of drugs, is the limited stability of these molecules. The stability depends on many factors, such as pH, temperature, and the nature of the aglycon (15). Our experiments with AcMPAG showed that rapid hydrolysis of this metabolite occurs when plasma is stored under physiological pH at room temperature as well as at 4 or -20 °C. Only acidification to pH 2.5 immediately after collection of the samples, followed by storage at -20 °C, provides satisfactory stabilization of AcMPAG for longer time periods (up to 1 month). Furthermore, the acidified samples were found to be stable at room temperature, which is of importance with respect to the handling and assay procedures. Concomitant loss of AcMPAG because of hydrolysis may lead to falsely increased MPA concentrations in plasma samples. This can be of importance, particularly when samples obtained 4–8 h after MMF intake are analyzed, because a major influence on the magnitude of this error will certainly be the ratio between MPA and AcMPAG concentrations in the plasma. Our results reconfirm findings with other acyl glucuronide metabolites (8)(9)(15) and demonstrate that careful collection, storage, and handling procedures should be used during the analysis of both AcMPAG and MPA to ensure the accurate collection of pharmacokinetic and toxicologic data when studies are performed with the immunosuppressant MPA.
In conclusion, the data presented here provide an analytical means to determine the AcMPAG concentrations in plasma and may allow investigation into their relevance with respect to both the immunosuppression and side effects related to MMF therapy.
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Acknowledgments |
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Footnotes |
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1 Nonstandard abbreviations: MPA, mycophenolic acid; MMF, mycophenolate mofetil; 7-O-MPAG, 7-O-glucuronide of mycophenolic acid; AcMPAG, acyl glucuronide of mycophenolic acid; MPAC, carboxybutoxy ether of MPA; UV, ultraviolet; and dk, critical difference. 
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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