Effect of clinical condition and mycophenolate mofetil on plasma retinol, α-tocopherol and β-carotene in renal transplant recipients.

Abstract

Plasma antioxidant vitamins (retinol, α-tocopherol, β-carotene) were measured to establish the influence of clinical condition and mycophenolate mofetil (MMF) treatment on the nutritional status of renal transplant recipients.
In 106 adult patients plasma vitamins were measured and 24-h diet history questionnaires were conducted. The MMF influence on plasma vitamins was verified in 61 patients.
The current dietary intakes of vitamins in daily food rations were lower than recommended. Plasma retinol was lower in patients suffering from gastrointestinal disorders (1.25 ±0.48 mg/l vs. 1.55 ±0.70 mg/l) and inversely associated with aminotransferases activity (p = 0.019) and creatinine clearance (p = 0.021). Retinol concentrations were positively associated with plasma creatinine (p = 0.027) and pharmacokinetic parameters of MMF phenyl glucuronide. β-Carotene concentrations were higher in women (0.39 ±0.46 mg/l vs. 0.28 ±0.23 mg/l; p = 0.041) and when MMF was co-administered with cyclosporine vs. tacrolimus (0.45 ±0.62 mg/l vs. 0.25 ±0.19 mg/l). Plasma α-tocopherol correlated negatively with the mycophenolic acid pre-dose concentration (p = 0.027) and was significantly lower in patients treated with calcineurin inhibitors (8.90 ±5.23 mg/l vs. 12.25 ±5.62 mg/l). A positive correlation was observed between α-tocopherol levels and aspartate aminotransferase (p = 0.006). In multivariate regression aspartate aminotransferase and MMF treatment significantly influenced retinol (p < 0.001).
The MMF treatment was associated with significantly lower retinol concentrations. The gastrointestinal disorders occurrence in MMF-treated patients may cause a decrease in retinol absorption. Diet adjustment and/or vitamin A supplementation should be considered.

Full text

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Effect of clinical condition and mycophenolate mofetil on
plasma retinol, α-tocopherol and β-carotene in renal
transplant recipients
Jolanta Kamińska1, Joanna Sobiak1, Maciej Głyda2, Grażyna Duda3, Małgorzata Nogala-Kałucka4,
Aleksander Siger4, Maria Chrzanowska1
Abstract
Introduction: Introduction: Plasma antioxidant vitamins (retinol, α-tocopherol, β-carotene)
were measured to establish the influence of clinical condition and mycophenolate
mofetil (MMF) treatment on the nutritional status of renal transplant recipients.
Material and methods: Material and methods: In 106 adult patients plasma vitamins were measured
and 24-h diet history questionnaires were conducted. The MMF influence on
plasma vitamins was verified in 61 patients.
Results: Results: The current dietary intakes of vitamins in daily food rations were low-
er than recommended. Plasma retinol was lower in patients suffering from gas-
trointestinal disorders (1.25 ±0.48 mg/l vs. 1.55 ±0.70 mg/l) and inversely asso-
ciated with aminotransferases activity (p = 0.019) and creatinine clearance
(p = 0.021). Retinol concentrations were positively associated with plasma cre-
atinine (p = 0.027) and pharmacokinetic parameters of MMF phenyl glucuronide.
β-Carotene concentrations were higher in women (0.39 ±0.46 mg/l vs. 0.28
±0.23 mg/l; p = 0.041) and when MMF was co-administered with cyclosporine
vs. tacrolimus (0.45 ±0.62 mg/l vs. 0.25 ±0.19 mg/l). Plasma α-tocopherol cor-
related negatively with the mycophenolic acid pre-dose concentration (p = 0.027)
and was significantly lower in patients treated with calcineurin inhibitors (8.90
±5.23 mg/l vs. 12.25 ±5.62 mg/l). A positive correlation was observed between
α-tocopherol levels and aspartate aminotransferase (p = 0.006). In multivariate
regression aspartate aminotransferase and MMF treatment significantly influ-
enced retinol (p < 0.001).
Conclusions: Conclusions: The MMF treatment was associated with significantly lower retinol
concentrations. The gastrointestinal disorders occurrence in MMF-treated
patients may cause a decrease in retinol absorption. Diet adjustment and/or
vitamin A supplementation should be considered.
Key words: Key words: antioxidant vitamins, clinical condition, mycophenolate mofetil, renal
transplantation, nutritional status.
Introduction
Malnutrition in renal transplant recipients intensifies coexisting dis-
eases, deteriorates prognosis, increases mortality and morbidity as well
CorresCorresp pondin
Assoc. Prof.
Maria Chrzanowska PhD
Department
of Physical Pharmacy
and Pharmacokinetics
Poznan University
of Medical Sciences
6 Swiecickiego
60-781 Poznan, Poland
Phone: +48 61 854 64 36
Fax: +48 61 854 64 30
E-mail: mchrzan@ump.edu.pl
onding g author: author:
Clinical research
1Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical
Sciences, Poland
2Department of Transplantology and General Surgery, District Hospital, Poznan, Poland
3Department of Bromatology, Poznan University of Medical Sciences, Poland
4Department of Biochemistry and Food Analysis, Poznan University of Life Sciences,
Poland
S Su ub bmitted: mitted: 20 April 2011
A Acceccep pted: ted: 14 January 2012
Arch Med Sci 2012; 8, 2: 256-262
DOI: 10.5114/aoms.2012.28553
Copyright © 2012 Termedia & Banach

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Arch Med Sci 2, April / 2012 257
as the cost of health care and, generally, it deteri-
orates the life quality of patients [1]. Malnutrition
may result from gastrointestinal disorders, often
leading to digestion and absorption disorders, as
well as from concomitant diseases such as post-
transplant diabetes, chronic liver disease and infec-
tions, which often occur in transplant recipients due
to the various administered medications [2-6]. The
majority of complications may be prevented or
treated by early nutritional intervention and follow-
up. Therefore, evaluation of the nutritional status
as well as the analysis of risk factors concerning
malnutrition have become more prevalent among
physicians [1].
One of the factors influencing nutritional status
in patients after solid organ transplantation may
be the immunosuppressive agent administered. At
present, mycophenolate mofetil (MMF) is the most
widely used antiproliferative drug after solid organ
transplantation [7]. The MMF was also found to be
beneficial in children with idiopathic nephritic syn-
drome, primary glomerulonephritis and auto-anti-
body associated glomerulonephritis. Some authors
recommend MMF to be a part of the standard treat-
ment regimen for lupus nephropathy [8]. The MMF
is often co-administered with calcineurin inhibitors
(CNI) and corticosteroids [7, 9]. After oral adminis-
tration, pharmacologically inactive MMF is rapidly
and entirely hydrolyzed into an active metabolite,
mycophenolic acid (MPA) [2, 10], which is further
converted into an inactive phenyl glucuronide
(MPAG) [11]. Although the appropriate diet may be
contributory in reducing metabolic disorders [12],
which often occur during immunosuppressive ther-
apy, there have been, to our knowledge, few stud-
ies concerning MMF treatment and the nutritional
status of renal transplant recipients.
Some of the disorders noted have been associat-
ed with oxidative stress. Therefore, an appropriate
intake of antioxidant vitamins (tocopherols, retinol
and carotenoids) may help prevent diabetes melli-
tus, cardiovascular and central neurodegenerative
diseases as well as cancer [13-17]. However, in clini-
cal practice, vitamin concentrations are rarely deter-
mined in patients during the post-transplant period,
and there are few studies focusing on MMF [18].
The aim of the study was therefore to assess the
influence of clinical condition, MMF treatment and
the pharmacokinetics of its metabolites (MPA and
MPAG) on vitamin nutritional status (retinol, α-toco-
pherol and β-carotene) in renal transplant recipients.
Material and methods
PatientsPatients
The study included 106 renal transplant recipi-
ents aged 20-72 years in the late post-transplant
period. In all patients sex and clinical condition such
as diabetes, gastrointestinal disorders, liver func-
tion (alanine aminotransferase [ALT] and aspartate
aminotransferase activity [AST] above or below
36 U/l) as well as kidney function (plasma creati-
nine [Ccr] above or below 1.5 mg/dl; creatinine clear-
ance [CLcr] above or below 60 ml/min) in relation
to plasma vitamin concentrations were examined.
The MMF influence on plasma vitamins was stud-
ied in 61 renal transplant recipients aged 23-69 years
treated with MMF (MMF group) with cyclosporine
(CsA) (n = 28), tacrolimus (Tac) (n = 24) or without
CNI (n = 9). Almost all patients in this group were
treated with corticosteroids (n = 54). Additionally,
the results were compared with a group of 45 renal
transplant recipients aged 20-72 years, treated with
different immunosuppressive regimens excluding
MMF and mycophenolate sodium (non-MMF group).
Immunosuppressive regimens included corticos-
teroids (n = 42) in combination with CNI (n = 36),
azathioprine (n = 16) or sirolimus (n = 12). Clinical
characteristics of the patients are listed in Table I.
For vitamin analysis, blood samples from
patients were collected into EDTA tubes after an
overnight fast. The samples were centrifuged to
obtain plasma and stored at –20°C until analyzed.
The vitamin concentrations were analyzed in
order to establish whether MMF treatment or MPA
and MPAG pharmacokinetics could have influenced
vitamin concentrations.
The study was approved by the Bioethical Com-
mittee at Poznan University of Medical Sciences
and is in accordance with the Helsinki Declaration
of 1975. Informed consent was obtained from the
patients prior to initiating the study.
Determination of vitamins Determination of vitamins
The determination of plasma α-tocopherol,
retinol and β-carotene was based on standard
methods [19-21] with some modifications. The
reverse-phase HPLC method (Hewlett-Packard 1100)
with a Supelcosil LC-18-DB column was applied
for retinol and α-tocopherol analyses. The normal-
phase HPLC method (WATERS 600) with
a LiChrosorb Si 60 column was used for β-carotene
analysis. The vitamin concentrations of standard
solutions were prepared according to their
absorbance values (1 cm/1%) (for retinol 1835 at
325 nm, for α-tocopherol 75.8 at 290 nm, for
β-carotene 2590 at 450 nm).
Into 200 μl of plasma, 20 μl of internal standard
(IS) (retinol acetate 25 mg/l in ethanol) was added.
For β-carotene determination, 20 μl of hexane was
added instead of IS. Subsequently, 500 μl of water,
500 μl of ethanol with 0.04% of BHT (2,6-di-tert-
butyl-4-methylphenol) and 1000 μl of hexane with
0.04% BHT were added. The resulting solutions
were shaken for 5 min, vortex-mixed (10 min at
1000 × g) and 700 μl of the organic layer was col-
Effect of clinical condition and mycophenolate mofetil on plasma retinol, α-tocopherol and β-carotene in renal transplant recipients

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Arch Med Sci 2, April / 2012
lected. The hexane was evaporated to dryness
under nitrogen at 40°C. The residue was dissolved
in 200 μl of mobile phase (methanol with 0.025%
of BHT for retinol and α-tocopherol; hexane with
dioxane in 97 : 3 volumetric ratio for β-carotene),
transferred into vials and 20 μl was injected into
the HPLC system. For retinol and α-tocopherol, the
flow rate was 1.2 ml/min and the column was ther-
mostatic at 20°C with simultaneous ultraviolet
(325 nm for retinol) and fluorescence (excitation
wavelength of 295 nm and emission wavelength of
325 nm for α-tocopherol) detections. For β-carotene,
the flow rate was 1.5 ml/min with photodiode-array
ultraviolet detection (450 nm). The sample prepa-
ration was processed under a stream of nitrogen
and in dim light.
The inter-day precision, expressed as mean coef-
ficient of variation, was 7.4% for retinol (within con-
centration range 0.05-2.00 mg/l), 8.8% for α-toco-
pherol (within concentration range 1.0-30.0 mg/l)
and 7.8% for β-carotene (within concentration range
0.1-2.0 mg/l). The inter-day absolute accuracy was
3.5%, 5.7% and 4.1% for retinol, α-tocopherol and
β-carotene, respectively.
Pharmacokinetic parameters of mycophenolate
mofetil metabolites mofetil metabolites
Pharmacokinetic parameters of mycophenolate
For pharmacokinetic analyses plasma MPA and
MPAG concentrations were determined using the
HPLC method described previously [22, 23]. The fol-
lowing pharmacokinetic parameters for MPA and
MPAG were calculated: pre-dose concentration (C0),
maximum concentration (Cmax) and area under the
plasma concentration – time curve from 0 to 4 h
(AUC0-4 h) using the linear trapezoidal rule based on
six time points determination (before the morning
dose of MMF, 40 min, 1, 2, 3, and 4 h after dosing).
Pharmacokinetic parameters were normalized
to the MMF dose (per gram of MMF) (data not
shown).
Dietary intakeDietary intake
Each patient was subjected to a diet history
questionnaire to estimate 24-h food intake on the
day preceding the collection of blood samples. The
antioxidant vitamin intakes were analyzed on the
basis of the patients’ dietary history using Microsoft
Access 2000 databases, which are the extended
version of ‘Tables of food composition and nutritive
value’ [24]. The reference norms of 10 mg/day,
1 mg/day and 5 mg/day for α-tocopherol, retinol
and β-carotene, respectively, were assumed [25].
Statistical analysisStatistical analysis
All statistical tests were performed using Sta-
tistica software version 8.0 (StatSoft) and a p val-
ue lower than 0.05 was considered significant. Nor-
mality was determined by the Shapiro-Wilk test.
The differences between variables were estimated
using the Mann-Whitney test and for normally dis-
tributed data Student’s t test was applied. The
results are presented as mean ± standard devia-
tion (SD). The correlations of data were tested using
Pearson or Spearman correlation analysis for nor-
mally and non-normally distributed data, respec-
tively. Pearson’s χ2test was used for the evalua-
P ParameterarameterMMMMF F g grouroup p ( (n n = = 61)N Non on- -MM61)MMF F g grouroup p ( (n n = = 45)A All ll p patients atients ( (n n = = 106)45) 106)
Age [years] 43 ±12* 49 ±13*46 ±13
Post-transplant period [years]4.7 ±2.9*6.6 ±3.1* 5.5 ±3.1
Body weight [kg] 74.9 ±16.770.0 ±13.672.9 ±15.6
BMI [kg/m2]25.9 ±4.724.8 ±4.125.5 ±4.5
Creatinine concentration [mg/dl]1.80 ±0.691.76 ±0.741.78 ±0.70
Creatinine clearance [ml/min]58.4 ±24.451.5 ±19.755.5 ±22.7
Alanine aminotransferase [U/l]31.5 ±21.531.3 ±17.931.4 ±20.0
Aspartate aminotransferase [U/l]26.6 ±10.1 26.1 ±10.426.4 ±10.2
N Num umb ber o er of f p patientsatients
Sex (male/female) 34/27*19/26*53/53
CsA/Tac 28/2421/1549/39
Corticosteroids treatment 54 (88.5%)42 (93.3%)96 (90.6%)
Gastrointestinal disorders 45 (73.8%) 22 (48.9%)67 (63.2%)
Diabetes18 (29.5%)13 (28.9%) 31 (29.2%)
*p < 0.05 (MMF group vs. non-MMF group); BMI – body mass index, CsA – cyclosporine, MMF – mycophenolate mofetil, Tac – tacrolimus
T Ta ab ble Ile I. . Characteristics of patients included in the study (mean ± SD)
Jolanta Kamińska, Joanna Sobiak, Maciej Głyda, Grażyna Duda, Małgorzata Nogala-Kałucka, Aleksander Siger, Maria Chrzanowska

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Arch Med Sci 2, April / 2012 259
Effect of clinical condition and mycophenolate mofetil on plasma retinol, α-tocopherol and β-carotene in renal transplant recipients
tion of qualitative data. Multivariate regression
analysis was applied to evaluate the interactions
between several variables and their influence on
the levels of plasma antioxidant vitamins.
Results
Plasma retinol concentrations ranged from
0.58 mg/l to 3.83 mg/l and were statistically lower
in patients treated with MMF compared to the non-
MMF group. Plasma retinol levels were also found
to be significantly lower in patients suffering from
gastrointestinal disorders. Retinol concentrations
were statistically higher when CLcrwas lower than
60 ml/min and when Ccrwas above 1.5 mg/dl. The
ALT above 36 U/l was associated with lower retinol
levels (Table II). Retinol concentrations were nega-
tively associated with AST and positively with MPAG
AUC0-4 hand MPAG C0(Table III).
Plasma α-tocopherol concentrations ranged from
values below the lower limit of quantification
(LLOQ) to 25.63 mg/l. The concentrations of α-toco-
pherol were significantly lower in patients treated
with CNI (Table II). Moreover, a positive correlation
was observed between α-tocopherol levels and AST.
Plasma α-tocopherol concentrations correlated neg-
atively with MPA C0(Table III).
β-Carotene concentrations ranged from values
below the LLOQ to 3.22 mg/l. Despite the lack of
difference in dietary intake between men and
women, β-carotene concentrations were higher in
women and when MMF was co-administered with
CsA compared to MMF co-administered with Tac.
The concentrations of β-carotene were significant-
ly lower in patients suffering from diabetes and
from gastrointestinal disorders (Table II).
We also verified whether MMF treatment and
pharmacokinetics of MMF metabolites (MPA and
MPAG) correlate with patients’ clinical condition.
MMF treatment was associated with more frequent
gastrointestinal disorders (Table I). Additionally,
some MPA and MPAG pharmacokinetic parameters
correlated with liver or kidney function. MPA C0
was inversely dependent on ALT (p = 0.018),
AST (p = 0.050) and CLcr(p < 0.001), while all MPAG
P Parameterarameter
n n
Retinol Retinol
[ [m mg/ g/l l]
V Value oalue of f p p
α-T -Toco ocop pherol
[[m mg/ g/l l]
herol
]
V Value oalue of f p p
β- -Carotene Carotene
[[m mg/ g/l l] ]
V Value oalue of f p p
]
All patients1061.56 ±0.76 9.47 ±5.420.34 ±0.37
MMFYes 611.22 ±0.45 < 0.001 9.39 ±4.850.812 0.32 ±0.430.200
No452.03 ±0.869.59 ±6.19 0.35 ±0.26
MMF withCsA 281.12 ±0.390.2209.77 ±4.990.4840.45 ±0.620.046
Tac241.28 ±0.519.16 ±5.170.25 ±0.19
CNIYes881.58 ±0.81 0.8078.90 ±5.230.0260.36 ±0.390.153
No 181.47 ±0.46 12.25 ±5.62 0.24 ±0.16
Gastrointestinal Yes
disorders
67 1.25 ±0.480.049 9.35 ±5.320.533 0.26 ±0.180.031
No 391.55 ±0.7010.34 ±5.560.46 ±0.56
CLcr[ml/min]< 6071 1.68 ±0.830.021 8.93 ±5.560.108 0.36 ±0.430.853
≥ 60 351.32 ±0.54 10.58 ±5.040.29 ±0.20
Ccr[mg/dl]> 1.5 561.70 ±0.820.027 9.04 ±6.000.327 0.37 ±0.450.296
≤ 1.5 50 1.40 ±0.669.96 ±4.71 0.30 ±0.25
ALT [U/l]> 36 28 1.35 ±0.740.01910.03 ±4.400.322 0.28 ±0.220.311
≤ 3678 1.64 ±0.76 9.10 ±5.670.32 ±0.24
AST [U/l]> 36 13 1.36 ±0.510.491 11.05 ±3.280.190 0.23 ±0.160.170
≤ 36 931.59 ±0.799.16 ±5.580.32 ±0.24
Sex Male531.53 ±0.77 0.7509.42 ±5.30 0.8130.28 ±0.23 0.041
Female 531.59 ±0.76 9.53 ±5.590.39 ±0.46
DiabetesYes311.64 ±0.830.4189.17 ±5.590.9290.25 ±0.230.001
No75 1.54 ±0.759.25 ±5.340.34 ±0.24
MMF – mycophenolate mofetil, CNI – calcineurin inhibitors, CsA – cyclosporine, Tac – tacrolimus, CLcr– creatinine clearance, Ccr– plasma crea-
tinine, ALT – alanine aminotransferase, AST – aspartate aminotransferase
T Ta ab ble II
tered and patients’ clinical condition
le II. . Concentrations of retinol, α-tocopherol and β-carotene (mean ± SD) in relation to MMF, CNI co-adminis-

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Arch Med Sci 2, April / 2012
pharmacokinetic parameters (AUC0-4 h, C0and Cmax)
were inversely dependent on CLcr(CLcr> 60 ml/ min
and CLcr< 60 ml/min) (p < 0.001 for each pharma-
cokinetic parameter).
The factors which significantly influenced the
concentrations of vitamins as well as MMF metabo-
lites in univariate analysis were analyzed in multi-
variate regression. It was found that the influences
of some factors, e.g. diabetes and gastrointestinal
disorders on β-carotene concentration, CLcron
retinol concentration, and kind of CNI applied on
α-tocopherol, were statistically insignificant in mul-
tivariate regression. However, in the same way as
in the univariate analysis, the significant influence
of AST and MMF treatment on retinol concentra-
tion (p < 0.001) as well as the β-carotene concen-
tration dependence on sex (p = 0.037) were also
observed in the multivariate regression models. In
the multivariate regression analysis β-carotene was
not dependent on type of CNI co-administered.
The current dietary intakes of studied vitamins
in the daily food ration showed lower than recom-
mended intakes in all studied patients. Moreover,
similar intakes of analyzed vitamins were observed
in patients treated and not treated with MMF as
well as within the MMF group in relation to CNI
applied (Table IV).
Discussion
The determination of plasma vitamins consti-
tutes part of a study concerning the influence of
MMF on the nutritional status of renal transplant
recipients. Although the concentrations of retinol,
β-carotene and α-tocopherol detected in our study
are comparable to those previously described, the
latter concerned different populations or groups of
patients [18, 19, 21, 26, 27]. Our results showed that
the β-carotene concentration was dependent on
sex. This corroborates the findings of other authors
[28-30]. Although some studies indicated a rela-
tionship between retinol [29] as well as α-tocopherol
[30] and gender, we found no such correlation.
In our study only retinol concentrations were
lower in patients treated with MMF. We did not
observe any differences in α-tocopherol and
β-carotene concentrations between the MMF and
non-MMF group. However, β-carotene was depend-
ent on the administered CNI since β-carotene con-
centrations were significantly lower in patients
treated with MMF and with Tac compared to those
P Parameterarameter
n n
Retinol Retinol
[ [m mg/ g/l l]
α α-T -Tocoocop pherol herol
[ [m mg/ g/l l]
β β- -Carotene Carotene
[[m mg/ g/l l] ]]]
rrpprrpprrpp
ALT [U/l]106–0.1450.1400.0510.603 –0.1550.114
AST [U/l]106–0.2480.0110.265 0.006 –0.1370.165
MPA AUC0-4 h[mg×h/l]610.082 0.534–0.152 0.2470.151 0.249
MPA C0[mg/l] 610.2110.105 –0.2860.027 0.0210.875
MPAG AUC0-4 h[mg×h/l]61 0.3120.0260.0250.8610.1580.267
MPAG C0[mg/l]61 0.2950.0350.0710.6210.0710.618
ALT – alanine aminotransferase, AST – aspartate aminotransferase, MPA – mycophenolic acid, AUC0-4 h– area under the plasma concentration
– time curve from 0 to 4 h, C0– predose concentration, MPAG – 7-O-mycophenolic acid glucuronide
T Ta ab ble III le III. . Univariate regression analysis for retinol, α-tocopherol and β-carotene in relation to MMF metabolites phar-
macokinetic parameters and patients’ clinical condition
V Vitamin itaminMM MMF* F*MMMMF F in com in comb bination withination with*AAll ll p patients atients
((n n = = 106)
*
Y Yes es ( (n n = = 61)NNo o ( (n n = = 45) 61)45) Cs CsA A ( (n n = = 28)TTac ac ( (n n = = 24)28) 24)
106)
Retinol [mg]0.79 ±0.62 0.80 ±0.600.88 ±0.790.68 ±0.300.79 ±0.61
%RDA 87.2 ±66.4 88.3 ±60.595.9 ±81.1 76.2 ±35.587.7 ±63.7
α-Tocopherol[mg]7.10 ±4.41 7.63 ±5.28 7.47 ±5.536.59 ±3.487.32 ±4.77
%RDA 73.7 ±44.280.3 ±54.177.0 ±55.669.3 ±35.276.4 ±48.5
β-Carotene[mg]0.20 ±0.460.13 ±0.17 0.22 ±0.600.13 ±0.18 0.17 ±0.37
%RDA40.6 ±92.8 26.0 ±34.5 44.3 ±120.726.5 ±36.5 34.5 ±74.2
MMF – mycophenolate mofetil, CsA – cyclosporine, Tac – tacrolimus, RDA – recommended daily allowance; *differences statistically insignificant
T Ta ab ble I
with CNI
le IV. V. Dietary intake of antioxidant vitamins in patients treated in relation to MMF and MMF co-administered
Jolanta Kamińska, Joanna Sobiak, Maciej Głyda, Grażyna Duda, Małgorzata Nogala-Kałucka, Aleksander Siger, Maria Chrzanowska

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Arch Med Sci 2, April / 2012261
Effect of clinical condition and mycophenolate mofetil on plasma retinol, α-tocopherol and β-carotene in renal transplant recipients
who received the MMF and CsA regimen. To our
knowledge, ours is the first such study in adult
patients; however, in children [31] there were no
differences observed in β-carotene concentrations
in relation to CNI applied, probably due to the small
number of patients in particular groups (14 and
9 patients for CsA and Tac, respectively).
Additionally, we observed lower retinol as well
as β-carotene concentrations in patients suffering
from gastrointestinal disorders. More frequent gas-
trointestinal disorders in patients treated with MMF
appeared to have led to a decrease in retinol
absorption.
Our results indicate that plasma retinol may be
associated with kidney function. High retinol con-
centrations were related to increased Ccrand
decreased CLcr. Furthermore, we observed positive
correlations between retinol concentration and MPAG
pharmacokinetic parameters, which may have result-
ed from the MPAG and retinol concentration depend-
ence on renal function. These correlations are con-
sistent with those of other authors [26, 32, 33]. In
fact, Botella-Carretero et al. [26] described a positive
correlation between the retinol concentration and
Ccr(r = 0.464; p < 0.001) in 80 obese patients (BMI
≥ 40 kg/m2) suffering from non-alcoholic fatty liver
disease. Gavrilov et al. [32] showed in multiple myelo-
ma patients, and Abahusain et al. [33] in diabetics,
a higher serum retinol concentration associated
with chronic renal insufficiency. It may suggest
a decreased retinol elimination in these patients.
In addition, our results indicate that plasma
retinol may also be related to liver function, as low
retinol concentrations were associated with high-
er ALT and AST activity. Botella-Carretero et al. [26]
found a negative correlation between retinol
and AST activity (r = –0.236; p = 0.036) and also
between retinol and ALT activity (r = –0.241;
p = 0.032). Consequently, the authors suggested
a protective retinol effect on the liver.
Unlike other authors, we observed a positive cor-
relation between α-tocopherol and AST, whereas
we did not find any correlation with ALT. The rela-
tionship between ALT and α-tocopherol has been
presented in several studies [34-36], while a similar
relationship with AST has been described only in
one article [34]; however, the research was con-
ducted in rats. In some studies, the favorable impact
of vitamin E supplementation on either ALT [34, 35]
or AST decreases [34] was indicated. In addition, low
α-tocopherol concentration was stated to be a reli-
able marker of hepatocyte damage, independently
of the increase in aminotransferase activity [36].
The negative correlation between α-tocopherol
and MPA C0may be caused by the dependence of
α-tocopherol and MPA C0on AST. The present study
seems to be the first to report an influence of MMF
on α-tocopherol.
In the present study, the significantly lower
β-carotene concentrations in diabetic patients cor-
roborates published data [37-39]. It makes our
results more relevant, as the protective role of
β-carotene in diabetes prophylaxis has been sug-
gested by many authors [37-41].
In conclusion, we found that MMF treatment sig-
nificantly influences retinol concentrations. MMF
treatment as well as the incidence of gastroin-
testinal disorders were associated with lower plas-
ma retinol concentrations, which may be caused by
decreased retinol absorption. Diet adjustment
and/or including vitamin A supplementation should
be considered in such patients.
Acknowledgments
This study was supported by Grant No. 501-02-
03306413-02324-50382 from Poznan University of
Medical Sciences. Mycophenolic acid phenyl glu-
curonide (MPAG) for analytical purposes was kindly
supplied by Roche Pharmaceuticals (Palo Alto, USA).
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