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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Abstract:  The risk of acute rejection in patients with higher exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), might be due to inosine 5′-monophosphate dehydrogenase (IMPDH) polymorphisms. The correlations with subclinical acute rejection, IMPDH1 polymorphisms and MPA exposure on day 28 post-transplantation were investigated in 82 Japanese recipients. Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times. There were no significant differences in the incidence of subclinical acute rejection between IMPDH1 rs2278293 or rs2278294 polymorphisms (= 0.243 and 0.735, respectively). However, in the high MPA night-time exposure range (AUC >60 μg·h/ml and C 1.9 μg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A, A/G and G/G genotypes (each = 0.019), but not the IMPDH1 rs2278294 genotype. In the higher daytime MPA exposure range, patients with the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In patients with the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The risk of subclinical acute rejection for recipients who cannot adapt in therapeutic drug monitoring (TDM) of MPA seems to be influenced by IMPDH1 rs2278293 polymorphism. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.

Mycophenolic acid (MPA), the active metabolite of the pro-drug mycophenolate mofetil (MMF), is a standard immunosuppressive drug used in patients after renal transplantation [1,2]. MPA is a selective inhibitor of the enzyme inosine 5′-monophosphate dehydrogenase 1 (IMPDH1) that plays an important role in the de novo biosynthesis of guanine nucleotides. MPA inhibits T- and B-lymphocyte proliferation by inhibition of IMPDH activity, which is responsible for its immunosuppressive effect.

In order to prevent acute rejection, therapeutic drug monitoring (TDM) of MPA has been performed. A therapeutic target range for MPA between 30 and 60 μg·h/ml for the area under the concentration-time curve from 0 to 12 hr (AUC0-12) has been recommended [2,3]. In renal transplant recipients, reduced acute rejection rates are associated with MPA AUC0-12 above 30 μg·hr/ml [3–7]. In addition, in renal transplant recipients receiving tacrolimus and MMF, trough concentration (C0) as determined by high-performance liquid chromatography (HPLC) above 1.9 μg/ml of MPA is reported to have an AUC0-12  30 μg·hr/ml [2,3].

However, it is well-known that acute rejection may still occur in recipients with MPA AUC0-12  30 μg·hr/ml or C 1.9 μg/ml and moreover in those with AUC0-12 > 60 μg·hr/ml. Namely, some patients cannot adapt in TDM. Such patients might have high IMPDH activity in lymphocytes and therefore might not exhibit adequate inhibition of T- and B-lymphocyte proliferation by MPA. Although IMPDH activity decreased following exposure to high MPA concentrations [8–10], Glander et al. demonstrated an association between high pre-transplantation IMPDH activity and acute rejection [11]. In addition, patients with low IMPDH activity require a lower MMF dosage to obtain the same immunosuppressive effect [11]. Thus, pharmacodynamic monitoring of IMPDH activity seems suitable in order to individualise MMF therapy. However, the practical difficulty and time-consuming nature of IMPDH assays compared to methods for determining MPA plasma concentrations are a serious drawback and hinder implementation of this approach [12]. Several single-nucleotide polymorphisms of IMPDH have been reported [13–17]. Wang et al. reported that the rs2278293 and rs2278294 single-nucleotide polymorphisms within intron 7 of IMPDH1 are significantly associated with the incidence of biopsy-proven acute rejection 1 year after renal transplantation [17]. Therefore, the risk of acute rejection in patients exhibiting the higher MPA exposure range might be caused by IMPDH polymorphisms. However, the associations between IMPDH genetic polymorphisms, MPA exposure and early clinical events after renal transplantation have not yet been elucidated.

Our aim in this study was to investigate the correlations between IMPDH1 polymorphisms, MPA exposure (AUC0-12 or C0), and subclinical acute rejection on day 28 after renal transplantation in 82 Japanese recipients in order to explore the relationship between pharmacogenetics, pharmacokinetics and pharmacodynamics of MPA.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients and protocols.  Eighty-two Japanese renal transplant recipients were selected to participate in this study. The study protocol was approved by the Ethics Committee of Akita University Hospital and all recipients gave written informed consent. Patient characteristics are listed in table 1. The eligibility criteria for the study were as follows: (i) first living-donor transplantation; (ii) identical immunosuppressive regimens, including tacrolimus (Prograf®; Astellas Co. Ltd, Tokyo, Japan), MMF (Cellcept®; Chugai Pharmaceutical Co. Ltd, Tokyo, Japan), and steroids; and (iii) ABO compatible.

Table 1.    Clinical characteristics of renal transplant recipients.
  1. Data are mean values ± SD (range), except for the number of patients.

Patients (male/female)48/34 
Age (years)44.6 ±12.8(20–70)
Weight (kg)57.2±12.8(38–118)
Aspartate transaminase (IU/l)15.8 ±7.4(6–48)
Alanine transaminase (IU/l)20.0 ±16.8(2–108)
Total bilirubin (mg/dl)0.4±0.2  (0.1–1.1)
Serum albumin (g/dl)4.1±0.4  (3.1–5.0)
Serum creatinine (mg/dl)1.5±1.0  (0.6–8.4)
Creatinine clearance (ml/min)56.2 ±22.4 (12.3–151)

Renal transplant recipients were given combination immunosuppressive therapy consisting of tacrolimus and 1.0, 1.5 or 2.0 g/day of MMF in equally divided doses every 12 hr at designated times (9:00 a.m. and 9:00 p.m.), but some patients could not tolerate this MMF dose due to diarrhoea. The daily tacrolimus dose was adjusted according to the clinical state of the patient. The whole blood-trough target level of tacrolimus was 15–20 ng/ml up to 2 weeks, 10–15 ng/ml up to 4 weeks and less than 10 ng/ml thereafter. Methylprednisolone was given to all recipients concomitantly, 500 mg on the day of surgery, 40 mg/day during the first week, then 20 mg/day of prednisolone in the second week, decreasing to 15 mg/day in the third week and 10 mg/day thereafter. On day 28 after renal transplantation, whole blood samples (5 ml) were collected by venipuncture just prior to and at 1, 2, 3, 4, 6, 9 and 12 hr after oral MMF and tacrolimus administration at 9:00 a.m. and 9:00 p.m. Plasma was isolated by centrifugation at 1900 × g for 15 min. and stored at −30°C until analysed. Meals were served at 7:30 a.m., 12:30 p.m. and 6:00 p.m. daily. Although the meal content (Japanese food) varied each day for each patient, the energy, fat, protein and water content were standardized (energy, 1700–2400 kcal; protein, 70–90 g; fat, 40–50 g; water, 1600–2000 ml) according to body weight.

Criteria of subclinical acute rejection due to MMF.  Diagnosis of acute rejection and chronic allograft nephropathy histological specimens were obtained by an allograft core biopsy without clinical events at the time of transplantation and on day 29 after transplantation. Histology of donor grafts at the time of transplantation did not show any findings of glomerulonephritis and interstitial fibrosis was less than 5% of the cortex. Clinical acute rejection with acute elevation in serum creatinine greater than 25% above baseline was not found in any recipient during the study period. Therefore, the definition of biopsy-confirmed acute rejection in this study was subclinical acute rejection with baseline and type IA changes according to the Banff classification [18]. Subclinical acute rejection was treated with intravenous methylprednisolone administration. There were no type II or III changes in any recipient. Serum creatinine levels were stable in all recipients 1 year after transplantation. The definition of chronic allograft nephropathy focused on subclinical progressive interstitial fibrosis and tubular atrophy (IF/TA) in type II (moderate) or III (severe) of the ‘05 Banff classification [18] with no evidence of any specific aetiology. Pathological diagnosis was performed by one nephro-pathologist (AK) who did not participate in the treatment or follow-up of recipients.

Genotyping.  DNA was extracted from a peripheral blood sample using a QIAamp blood kit (Qiagen, Hilden, Germany) and was stored at −80°C until analysed. The IMPDH1 rs2278293 A/G and rs2278294 A/G polymorphisms were determined by the direct-sequencing method procedure of Wang et al. [17] and a PCR restriction fragment length polymorphism (PCR-RFLP) procedure. Briefly, samples (20 μl) of a PCR mixture containing: 100 ng of genomic DNA template, 1.5 mM MgCl2, 0.5 μmol each of forward primer (5′-CCG GCT CTG ACC ACA CTT-3′) and reverse primer (5′-AGG AAA AGG CTG GAA GAA AGC-3′), 200 μM of dNTP mixture and 1.25 units of HotStar Taq DNA polymerase were amplified using an iCycler (Bio-Rad Laboratories, Inc., Tokyo, Japan). PCR conditions were: an initial denaturation step of 15 min at 95°C, 35 cycles of 30 sec at 95°C; 30 sec at 64°C; 30 sec at 72°C and a final extension step of 5 min at 72°C. For rs2278293 genotyping, the amplified PCR product was digested with 10 units of TspR I (New England BioLab, Beverly, MA, USA) for 3 hr at 37°C. Digested products were separated by electrophoresis on a 4% agarose gel and then stained with ethidium bromide. Genotype was determined by digestion pattern of PCR products by TspRI (A allele: 189 + 91 + 64 bp, G allele: 189 + 91 + 33 + 31 bp). The results obtained from the two methods were in complete accordance. For rs2278294 genotyping, the amplified PCR product was digested with 10 units of BamHI (New England BioLab, Beverly, MA, USA) for 3 hr at 37°C. Genotype was determined by digestion pattern of PCR products by BamHI (A allele: 87 + 277 bp, G allele: 364 bp). The PCR-RFLP genotypes were in complete accordance with those obtained from the direct-sequencing method of Wang et al. [17].

MPA assay.  Plasma concentrations of MPA were measured by HPLC [19]. The lower limit of quantification for MPA was 0.05 μg/ml. The coefficient of variation and accuracy for the inter- and intra-day assay for MPA were less than 9.6% and 9.3%, respectively.

Pharmacokinetic analysis.  Pharmacokinetic analysis of MPA was carried out with a standard non-compartmental model using WinNonlin (Pharsight Co., Mountain View, CA, USA, version 4.0.1). The total area under the observed plasma concentration-time curve (AUC0-12) was calculated using the linear trapezoidal rule. The pre-dose trough concentration (C0) was obtained directly from the profile.

Statistical analysis.  The results in summary of patients were expressed as the mean ± SD or number. The results in comparison between the three genotype groups was expressed as median (quartile 1–quartile 3) or number of patient. The chi-square test or Fisher’s exact test and the Kruskal–Wallis test were used to compare proportions of patients for clinicopathological and genotype factors. A p-value less than 0.05 was considered statistically significant. Statistical analyses were carried out using SPSS statistical software (SPSS Japan Inc., Tokyo, Japan, version 17.0).

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

According to our criteria of acute rejection (see methods section), clinical acute rejection was not found in any recipient within 1 month following transplantation. We therefore analysed the association between IMPDH1 polymorphisms, MPA exposure and subclinical acute rejection.

The IMPDH1 rs2278293 A/A, A/G and G/G genotypes were detected in 17 (20.7%), 38 (46.3%), and 27 (33%) of the 82 Japanese adult recipients, respectively. The IMPDH1 rs2278294 A/A, A/G and G/G genotypes were detected in 17 (20.7%), 40 (48.8%) and 25 (30.5%) of the 82 Japanese adult recipients, respectively. These were in Hardy-Weinberg equilibrium.

There were no significant differences in the incidence of subclinical acute rejection between the three IMPDH1 rs2278293 (three, eight and ten subclinical acute rejection) and 14, 30 and 17 (non-subclinical acute rejection) recipients had A/A, A/G and G/G genotypes, respectively, = 0.243 –table 2) or rs2278294 genotypes (five, 11 and five subclinical acute rejection) and 12, 29 and 20 (non-subclinical acute rejection) recipients had A/A, A/G and G/G genotype, respectively, = 0.735, table 3). In patients with MPA AUC0-12 range >60 μg·h/ml and MPA C 1.9 μg/ml during the night, there was a significant difference in the incidence of subclinical acute rejection between the three IMPDH1 rs2278293 genotypes (In AUC0-12 range >60 μg·h/ml, zero, two and five subclinical acute rejection) and six, 13 and four (non-subclinical acute rejection) recipients had A/A, A/G and G/G genotypes, respectively, = 0.019; in MPA C 1.9 μg/ml, three, four and ten (subclinical acute rejection) and 12, 24 and 11 (non-subclinical acute rejection) recipients had A/A, A/G and G/G genotypes, respectively, = 0.026, table 2). In the IMPDH1 rs2278293 genotype groups during the night, there were no differences between the profile regarding age, body weight and biochemical data (aspartate transaminase, alanine transaminase, bilirubin, albumin, serum creatinine and creatinine clearance, table 3).

Table 2.    The association of subclinical acute rejection, MPA exposure ranges and IMPDH1rs 2278293 polymorphism.
Subclinical acute rejectionIMPDH1 rs2278293NumberMPA AUC0-12 (μg hr/ml)MPA C0 (μg/ml)
<3030–60>60<1.9≥1.9
  1. Chi-square test or Fisher’s test for rejection versus IMPDH genotype in each MPA exposure range group.

  2. AUC0-12, area under the plasma concentration-time curve from 0 to 12 hr; C0, trough plasma concentration.

Daytime
Present/absentA/A 3/140/11/42/90/43/10
A/G 8/300/1 5/15 3/143/65/24
G/G10/170/13/6 7/102/18/16
p-values 0.243  0.841 0.230   0.394
A/A+A/G versus G/G p-values 0.113  0.651 0.181  0.238
A/A versus G/G p-values 0.198 >0.999 0.249  0.711
Night time
Present/absentA/A 0/33/50/60/2 3/12
A/G 0/3 6/14 2/134/6 4/24
G/G 0/1 5/125/40/610/11
p-values   0.911 0.019   0.026
A/A+A/G versus G/G p-values  >0.999 0.014  0.014
A/A versus G/G p-values   0.679 0.044  0.159
Table 3.    Clinical characteristics of recipients in IMPDH1rs 2278293 genotype groups
IMPDH1 rs2278293A/A A/G G/G  
  1. Data are expressed as median (quartile 1–quartile 3) or number of patient

  2. 1Chi-square test.

  3. 2Kruskal–Wallis test.

Night time patient number17 38 27  
Sex (male/female)11/6  19/19 18/9 0.34251
Age (years)46(42–57)43(32–55)47(32–55)0.65522
Weight (kg)53.5   (45.1–66.0)54.5   (47.7–62.5)56.3   (52.0–65.0)0.48042
Aspartate transaminase (IU/l)12(11–16)15(12–22)12(10–19)0.12002
Alanine transaminase (IU/l)13(11–22)17(12–32)12(8–22)0.15732
Total bilirubin (mg/dl)0.4   (0.3–0.6)0.4   (0.4–0.5)0.4   (0.3–0.5)0.62852
Serum albumin (g/dl)4.1   (3.9–4.4)4.3   (3.9–4.4)4.1   (3.9–4.4)0.44162
Serum creatinine (mg/dl)1.2   (1.0–1.6)1.2   (0.9–1.6)1.4   (1.1–1.7)0.26052
Creatinine clearance (ml/min)51.9   (38.6–70.2)56.0   (44.9–68.2)59.7   (39.4–65.8)0.79512

However, in both the day and night, there were no significant differences in the incidence of subclinical acute rejection between the IMPDH1 rs2278294 polymorphism in each of three groups classified according to the target range of the MPA AUC0-12 (table 4). Similarly, there were no significant differences in the incidence of subclinical acute rejection between the IMPDH1 polymorphism in each of the two groups classified according to the target range of the MPA C0 (table 4).

Table 4.    The association of subclinical acute rejection, MPA exposure ranges and IMPDH1rs 2278294 polymorphism
Subclinical acute rejectionIMPDH1 rs2278294NumberMPA AUC0-12 (μg h/ml)MPA C0 (μg/ml)
<3030-60>60<1.9≥1.9
  1. Chi-square test or Fisher’s test for rejection versus IMPDH genotype in each MPA exposure range group.

  2. AUC0-12, area under the plasma concentration-time curve from 0 to 12 hr; C0, trough plasma concentration.

Daytime
Present/absentA/A 5/120/02/73/50/2 5/10
A/G11/290/3 6/10 5/164/5 7/24
G/G 5/200/01/8 4/121/4 4/16
p-values 0.735 0.3370.744 0.682
A/A+A/G versus G/G p-values0.585 0.394>0.999 0.758
A/A versus G/G p-values0.714 >0.9990.647 0.451
Night time
Present/absentA/A 0/03/72/52/2 3/10
A/G 0/5 8/11 3/132/8 9/21
G/G 0/2 3/132/50/4 5/16
p-values  0.3300.818 0.842
A/A+A/G versus G/G p-values  0.313>0.999 >0.999
A/A versus G/G p-values  0.644>0.999 >0.999

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

In order to prevent acute rejection in recipients with low MPA exposure, TDM of MPA to control within the therapeutic range (between 30 and 60 μg·hr/ml of MPA AUC0-12) is performed. However, in recipients that cannot adapt in TDM, the cause of acute rejection with higher MPA exposure is unclear.

In the present study, in high nighttime MPA exposure (AUC0-12 > 60 μg·hr/ml and C 1.9 μg/ml), there was a significant difference in the incidence of subclinical acute rejection between IMPDH1 rs2278293 A/A+A/G and G/G genotypes (each = 0.014), and in the higher daytime MPA exposure range, the patients having the IMPDH1 rs2278293 G/G genotype also tended to develop subclinical acute rejection. In recipients having the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. Thus, the risk of subclinical acute rejection for recipients with higher MPA exposure seems to be significantly influenced by the IMPDH1 rs2278293 polymorphism. If IMPDH activity is high, MPA might not fully control lymphocyte proliferation even if high MPA exposure was maintained in the patients. This IMPDH1 single-nucleotide polymorphism might be one factor that could not be adapted to TDM of MPA and might be a decisive biomarker of intensity of IMPDH activity.

MPA pharmacokinetics has circadian rhythm [20]. Plasma concentrations of MPA during the night are significantly lower than those during the day [20,21], because the absorption rate of MPA is slower and the glucuronidation activity of MPA is higher at night than during the day [21]. Therefore, in the present study, 40 and 30 patients had AUC0-12 > 60 μg·h/ml during the day and at night, respectively. Our results do not show the necessity of monitoring MPA plasma concentrations at night. Patients with the IMPDH1 rs2278293 G/G genotype develop subclinical acute rejection even if high MPA plasma concentrations are maintained at night. A correlation between MPA plasma concentration and IMPDH1 rs2278293 polymorphism was clear at night. This correlation might be due to the influence of other immunosuppressive agents such as steroids at night. Consequently, the prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.

In patients within the therapeutic range between 30–60 μg·hr/ml of MPA AUC0-12, there was no association between subclinical acute rejection and IMPDH1 polymorphisms during the day and night. In the three combinations of immunosuppressive therapy consisting of tacrolimus, MMF and prednisolone, if the patient has high IMPDH activity in lymphocytes, other immunosuppressive agents such as tacrolimus and steroids could prevent subclinical acute rejection episodes. Therefore, the balance among blood or plasma concentration of these three agents in order to prevent subclinical acute rejection for recipients might be very important. Subclinical acute rejection, which is not controlled by tacrolimus, might be affected by IMPDH1 rs2278293 polymorphism.

On the other hand, IMPDH1 rs2278294 polymorphism was not able to predict subclinical acute rejection in the first month after transplantation. The majority of acute rejection episodes is reported to occur within the first month after transplantation [11]. If this single-nucleotide polymorphism is a decisive biomarker of intensity of IMPDH activity, the influence of this single-nucleotide polymorphism on the acute rejection should appear in the first month post-transplantation. IMPDH1 rs2278294 polymorphism might not become a decisive biomarker for subclinical acute rejection, but possible for biopsy-proven acute rejection. Long-term follow-up is needed to estimate the association between IMPDH1 rs2278294 polymorphism and subclinical acute rejection.

Our results might be interpreted within the context of the study limitations. The present study analysed the relation between MPA pharmacokinetics on day 28 and subclinical acute rejection on day 29 after renal transplantation. van Gelder et al. have reported that the MPA AUC0-12 on day 3 (= 0.009), but not month 1 (= 0.559), after transplantation relates to the incidence of biopsy-proven acute rejection within the first month [22]. In addition, Kiberd et al. also reported that MPA AUC0-12 < 30 μg·hr/ml on day 3 after transplantation correctly identified 79% of recipients suffering acute rejection within 3 months of transplantation [23]. In our present study on day 28 after transplantation, MPA exposure is high and was related with subclinical acute rejection. TDM of MPA on day 28 after transplantation may not be appropriate. A weakness of this study is that we do not have data of the MPA pharmacokinetics on day 3, day 7 and between days 10–14 after transplantation [3]. In addition, this present study was carried out in small clinical trials. In patients with AUC0-12 > 60 μg·hr/ml at night, when 0% and 16.7% of the patients with the IMPDH1 rs2278293 A/A and G/G genotype, respectively, develop subclinical acute rejection, a sample size of 42 is necessary to obtain a detection power of 80%. In the present study, our sample size of 30 with AUC0-12 > 60 μg·hr/ml at night is too small. Therefore, further study is necessary using a larger sample size. On the other hand, to our knowledge, there is no in vitro report of IMPDH1 rs2278293 and rs2278294 variants associated with enzymatic activity. Although the results of our present study and that of Wang et al. [17] show that the IMPDH1 rs2278293 G/G genotype seems to have higher enzymatic activity, further in vitro study might be necessary. In addition, Sombogaard et al. reported that the rs11706052 single-nucleotide polymorphism of the IMPDH2 gene is associated with an increased IMPDH activity in MMF-treated renal transplant recipients [24]. However, in our present study, only two of 82 patients were heterozygous for IMPDH2 rs11706052. Therefore, it is unlikely that IMPDH2 rs11706052 variant influences this present study; however, further study using other single-nucleotide polymorphisms of the IMPDH2 gene is also necessary.

Mycophenolic acid (MPA) is mainly glucuronized by uridine diphosphate-glucuronosyltransferases (UGTs) 1A9 into the phenolic MPA glucuronide. van Schaik et al. reported that the -275T/A and -2152C/T single-nucleotide polymorphisms of the UGT1A9 promoter can predict acute rejection when receiving treatment with fixed-dose MMF and tacrolimus [25]. The allele frequencies of UGT1A9–275T/A and –2152C/T in Caucasian renal recipients are reported to be 0.168 and 0.126, respectively [26]; however, these polymorphisms are not found in Asian populations and are not clinically important for MPA disposition in Asians [21,27,28]. In addition, in our previous report, polymorphisms of UGT1A9 intronic I399 were not associated with MPA plasma concentration in 80 Japanese renal transplant recipients after oral MMF administration [28]. Therefore, in Japanese subjects, UGT1A9 polymorphisms do not seem to influence interindividual variation of MPA pharmacokinetics.

In conclusion, our study suggested that IMPDH1 rs2278293 polymorphism might influence MPA pharmacodynamics. In recipients having the IMPDH rs2278293 A/A genotype, the risk of subclinical acute rejection episode tends to be low and the administration of MMF was effective. The prospective analysis of IMPDH1 rs2278293 polymorphism as well as monitoring of MPA plasma concentration after transplantation might help to improve MMF therapy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This work was supported by a grant from the Japan Society for the Promotion of Science (no. 20591894), Tokyo, Japan, the Japan Research Foundation for Clinical Pharmacology, Tokyo, Japan and the Research Foundation for Pharmaceutical Sciences, Tokyo, Japan.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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