Abstract
What is already known about this subject
Strategies that are more elaborate than measuring predose plasma concentrations are required for the therapeutic monitoring of mycophenolic acid (MPA).
Previous studies in healthy subjects and diabetes patients have suggested that MPA pharmacokinetics are influenced by gastric emptying, but this has not been demonstrated directly.
What this study adds
This study has investigated the relationship between gastric emptying, measured directly (using the 14C octanoate and 13C glycine breath tests) and the steady-state plasma concentration–time profile of MPA.
Delayed gastric emptying was associated with a longer tmax and lower Cmax, but total exposure to MPA was not affected.
The findings suggest that it could be misleading to rely fully on short-term (<2 h) limited sampling strategies for MPA therapeutic monitoring in recipients with gastric emptying disorders, the latter occurring relatively frequently in solid organ transplantation.
Aim
To investigate the effect of gastric emptying on the pharmacokinetics of mycophenolic acid (MPA) in renal transplant patients.
Methods
We assessed the effect of gastric emptying on the disposition of MPA in 27 stable renal allograft recipients at 2 years after transplantation. Gastric emptying was measured by the 14C-octanoate and 13C-glycine breath test.
Results
Delayed gastric emptying was associated with a significantly longer MPA tmax [1.0 (0.33–2.0) h vs. 0.5 (0.33–1.0) h; mean difference 0.39 h, 95% confidence interval (CI) 0.03, 0.75; P = 0.0289] and with a significant decrease in the maximum MPA concentration after dosing [10.6 (6.5–21.3) mg l−1vs. 20.1 (10.7–28.5) mg l−1; mean difference 6.5 mg l−1, 95% CI 2.1, 10.9; P = 0.0075]. Despite the substantial effect of delayed gastric emptying rates on MPA Cmax and tmax, total dose-interval exposure, measured by the MPA AUC0−4, was not affected by the rate of gastric emptying [20.4 (13.9–43.0) mg h−1 l−1vs. 22.4 (13.1–29.8) mg h−1 l−1].
Conclusion
Delayed gastric emptying was associatedwith a slower absorption of MPA, a longer time to reach peak concentrations and lower maximum concentrations. These effects should be taken into account when validating limited (<2 h) sampling strategies to estimate total MPA exposure, which could be unreliable when monitoring patients with gastric emptying disorders.
Keywords: absorption, gastric emptying, mycophenolic acid pharmacokinetics, therapeutic drug monitoring
Introduction
Mycophenolate mofetil (MMF) is an important component of current immunosuppressive drug regimens employed in renal transplantation. After oral administration, MMF is rapidly converted to mycophenolic acid (MPA), the active form of the drug [1]. MPA is a noncompetitive, selective and reversible inhibitor of inosine monophosphate dehydrogenase II, an essential enzyme for DNA synthesis in B and T lymphocytes [2]. MPA is metabolized by several forms of UDP-glucuronosyltransferase to its pharmacologically inactive 7-O-glucuronide (MPAG). The latter is excreted into the bile and reabsorbed by enterohepatic recirculation, a process which has been estimated to account for approximately 37% (range 10–61%) of total MPA exposure, and which is associated with a second peak in the MPA area under the time–concentration curve (AUC curve) [1, 3]. MPAG is also eliminated by the kidney, whereas only 5.5% of a dose of MMF is recovered in the faeces.
MPA exposure is characterized by a large intra- and interindividual variability that changes over time [3, 4]. Plasma MPA concentrations are influenced by renal graft function [4–6], serum albumin binding and concentration [6, 7], liver function [4, 8] and haemoglobin concentrations [6]. MPA is also subject to pharmacokinetic drug interactions with calcineurin inhibitors and mTOR inhibitors [9–11]. Other drugs can also influence the pharmacokinetics of MPA through interaction with the UDP-glucuronosyltransferases (UGTs) or the organic anion transporter MRP2 [1, 12–14]. Furthermore, genetic polymorphisms in the UGT1A9 gene encoding for MPA account at least in part for the interindividual variation in MPA exposure [15].
It has been reported that MPA tmax is slightly delayed and MPA Cmax is decreased by 25% in the fed state compared with when subjects are fasting. These effects were attributed to differences in the rate of gastric emptying [13]. It has also been demonstrated that MPA tmax is delayed in patients with diabetes mellitus [16, 17], again probably due to delayed gastric emptying [17].
It has been suggested that MPA exposure should be monitored routinely in renal allograft recipients in order to improve both graft outcome and avoid side-effects [18]. However, as MPA predose plasma concentrations do not adequately reflect total MPA exposure, more elaborate drug monitoring strategies (abbreviated AUC measurements or Bayesian estimates for MPA oral clearance) have been developed [4, 19]. In this respect, it is necessary to document the influence of gastric emptying on the concentration–time profiles of MPA. Failure to do this might lead to systematic errors in the AUC of MPA in these patients. Therefore, the current investigation was undertaken to assess directly the relationship between gastric emptying and MPA pharmacokinetics.
Materials and methods
Immunosuppressive drugs
Twenty male and seven female recipients of a cadaveric renal allograft (median age 60 years) consented to participate in this study. Recipients were treated with a standard maintenance immunosuppressive drug regimen of oral tacrolimus (Prograft; Fujisawa GmbH, München, Germany) in combination with MMF (CellCept; Roche Diagnostics, Mannheim, Germany) and oral methylprednisolone (Medrol; Upjohn, Puurs, Belgium). The daily tacrolimus dose was adjusted to achieve target predose blood concentrations of between 8 and 15 ng ml−1.
Inclusion and exclusion criteria
Patients who had received a single cadaveric donor kidney and were clinically stable were eligible for inclusion. Exclusion criteria were medical or surgical hepatic and gastrointestinal disorders, including active peptic ulcer disease and diabetes mellitus, which could interfere with the absorption, distribution, metabolism or excretion of MPA. Patients had to be free from biopsy-proven acute rejection for at least 6 months before the study, and any acute illness in the last 6 weeks was a contraindication for enrolment. Other exclusion criteria were treatment with drugs known to affect gastric emptying, a history of noncompliance, a known current drug, nicotine or alcohol addiction, and treatment with any drug documented to have a significant clinical effect on the absorption, distribution, metabolism and excretion of MMF. Approval was obtained from the ethics committee of the University of Leuven, Faculty of Medicine, and each patient gave written informed consent.
Clinical evaluation
Patients were monitored by physical examination and by the measurement of systolic and diastolic blood pressure, body weight, vital signs, and documentation of the results of laboratory tests. The use of any concomitant medication was noted. Renal allograft function was assessed using serum creatinine concentration and creatinine clearance calculated by the Cockcroft–Gault formula.
Pharmacokinetic and gastric emptying studies
Blood samples for MPA analysis were taken at predefined time points with simultaneous measurement of gastric emptying using 14C-octanoate/13C-glycine breath tests. Measurements were carried out at 24 months (n = 27) post transplantation. Owing to technical problems, one patient performed the 14C-octanoate breath test at 24 months but not the 13C-glycine test. Patients fasted overnight for at least 10 h and the morning dose of MMF was ingested at the start of the test meal (see below), 12 h after the previous dose. Twenty-two patients were treated with MMF 0.5 g every 12 h, three with 1 g bid, one with 0.75 g bid, and one patient received 0.25 g MMF bid. Dose adjustments were made earlier and for clinical reasons. Only patients who were stabilized on immunosuppressive therapy were studied.
Blood samples were taken through an intravenous catheter, immediately prior to the MMF dose (time point zero: C0) and at 20, 30, 40, 60, 75 and 90 min, 2 and 4 h post dose.
Metabolite analysis
Plasma concentrations of MPA and MPAG were determined using high-performance liquid chromatography (HPLC) with UV detection.
The supernatants were transferred to an autosampler vial and injected onto the HPLC. [MPA, MPAG and MPAC were a generous gift from Roche Palo Alto (Palo Alto, CA, USA). HPLC-grade acetonitrile was obtained from Fisher Scientific (Loughborough, UK) and water used was from Milli-Q Water System, filtered through a 0.45-µm regenerated cellulose membrane (Alltech Associates, Inc., Lokeren, Belgium). Metaphosphoric acid and trifluoroacetic acid were from Acros Organics (Geel, Belgium).]
A Finnigan Surveyor HPLC (Thermo Electron, Brussels, Belgium) equipped with a PDA-UV detector was used. Separation was performed using a Alltima HP C18 column (4.6 × 250 mm; 5 µm particle size; Alltech Associates, Inc.) and a Alltima HP C18 guard column (7.5 × 4.6 mm). Mobile phase A consisted of 0.1% trifluoroacetic acid in water and mobile phase B of 0.1% trifluoroacetic acid in acetonitrile. Separation was performed with the following gradient: 0–5 min (75%A); 5–16 min (20%A); 16–17 min (100%B); 17–20 min (100%B); 20–21 min (75%A); 21–25 min (75%A) at a column temperature of 40°C, an autosampler tray temperature of 25°C and a flow rate of 1.0 ml min−1. The detector wavelength was set at 254 nm and quantification was based on the peak area ratio of metabolite to internal standard (MPAC, the carboxybutoxy ether of MPA). Sample preparation consisted of the addition of 100 µl of internal standard (15 mg l−1) to 200 µl of plasma and vortex-mixing for 15 s. Cold metaphosphoric acid (100 µl of a 15% v/v solution) was then added and the sample was vortex-mixed for a further 15 s. The samples were centrifuged for 20 min at 15 000 g at 4°C.
The limit of detection (LOD) and limit of quantification (LOQ) of the method were defined empirically [20]. The LOD was 0.04 mg l−1 and 0.08 mg l−1 and the LOQ was 0.22 mg l−1 and 4.8 mg l−1 for MPA and MPAG, respectively. Interassay and intra-assay coefficients of variation were <5% for both MPA and MPAG. Recovery was 101% for MPA and 100% for MPAG. The analytic performance of the method was validated through participation in the International Mycophenolic Acid Proficiency Testing Scheme provided by Analytical Services International (London, UK).
Data analysis
Noncompartmental modelling with the linear up/log down method was used to determine the AUC0−4 of MPA and MPAG (WinNonlin 3.2 Pro software; (Pharsight, Mountain View, CA, USA). The AUC0−12 h of MPA was calculated from the 4-h AUC, using an algorithm previously validated in de novo renal recipients which explained 95% of the variance in AUC0−12 h with a mean percentage prediction error of 1.2 ± 11.1% (range −28% to 42.1%) and a mean absolute prediction error of 7.8 ± 8% (range 0.04–42.1%) [4]:
 |
Maximum blood concentration (Cmax), predose blood concentration (C0) and time to reach maximum blood concentration (tmax) were derived directly from the concentration–time profiles. An estimate of steady-state total body clearance (CL/F: total body clearance/F, where F is the fraction of dose absorbed) was obtained from the AUC0−12 h and the MMF dose.
The rate of gastric emptying of a standard mixed solid-liquid meal was measured using the combined 14C-octanoate/13C-glycine breath test [21, 22]. At all times, the investigators were blinded to the results of the pharmacokinetic gastric emptying studies. When the gastric emptying coefficient (GEC, determined by the area under the 14C or 13C recovery curve) for the 14C-octanoate test was <3.1 or the gastric emptying t1/2 was >75 min, the patient was considered to have delayed gastric emptying of solids [21]. The cut-off values for the diagnosis of delayed gastric emptying of fluids were a GEC of <3.0 or a gastric t1/2 of >55 min for the 13C-glycine breath test. These values were based on previous studies in healthy subjects [21].
Statistical analysis
Distributions for continuous data were evaluated using the Kolmogorov–Smirnov test, and parametric or nonparametric tests were then applied as appropriate. All data were expressed as median and range. Nonparametric statistics (Mann–Whitney U-test) were used to compare data [SAS 8.2 (SAS Inc., Cary, NC, USA) and Enterprise Guide 1.3 software], and simple regression analysis (Pearson's and Kendall's τ) for correlation of gastric emptying data with pharmacokinetic parameters. A P-value <0.05 was considered statistically significant.
Results
Patient demographics, transplantation-related characteristics, allograft function and relevant laboratory data at the time that the pharmacokinetic and gastric emptying studies were performed, are summarized in Table 1.
Table 1.
Demographic data, transplantation characteristics, allograft function and laboratory data in the 27 patients studied
| Median (range) | |
|---|---|
| Age at time of measurement (years) | 60 (30–72) |
| Sex (male/female) | 20/7 |
| Weight (kg) | 75.6 (45.7–110) |
| Height (cm) | 176 (149–196) |
| Time on renal replacement therapy (years) | 4.64 (1.17–24.38) |
| Retransplantation (N) | 2/27 |
| HLA-A, -B and -DR mismatches per patient | 2 (0–4) |
| Donor age (years) | 43 (8–64) |
| Donor sex (male/female) | 17/10 |
| Serum creatinine (mg dl−1) | 1.40 (0.89–5.22) |
| Creatinine clearance (ml min−1 1.73 m−2)* | 55 (8–87) |
| Serum albumin (g l−1) | 40.5 (36.1–49.4) |
| Haemoglobin (g l−1) | 10.8 (12.9–15.6) |
Data are expressed as median and range unless specified otherwise.
Calculated from the Cockcroft–Gault formula.
The GEC for fluids, measured by the 13C-glycine breath test, was 3.34 (3.01–3.59) in patients without (N = 11) vs. 2.56 (1.89–3.52) in patients with delayed gastric emptying (N = 15), and gastric t1/2 was 36 min (21–53) and 74 min (56–144), respectively. Using the 14C-octanoate breath test, the corresponding GEC values were 4.15 (3.37–4.81) vs. 3.49 (2.95–4.10) and the gastric t1/2 45 min (34–76) vs. 96 min (81–160), respectively, with respect to gastric emptying of solids.
Patients with delayed gastric emptying of fluids, as assessed by the 13C-glycine breath test, had significantly lower dose-corrected MPA maximum concentrations (Cmax) than patients with normal gastric emptying [mean difference 6.5 mg l−1, 95% confidence interval (CI) 2.1, 10.9] and needed longer to reach maximum MPA and MPAG concentrations (mean difference 0.39 h, 95% CI 0.03, 0.75). MPA AUC0−4, MPA AUC0−12, MPA CL/F, MPAG predose concentrations and MPAG AUC0−4 did not differ between the two groups (Table 2).
Table 2.
Comparison of MPA pharmacokinetic parameters between renal allograft recipients with normal and delayed gastric emptying, as measured with the 13C-glycine breath test for fluids
| 13C-glycine breath test | |||||
|---|---|---|---|---|---|
| Normal (n = 11) | Delayed (n = 15) | P-value | Mean difference (95% CI) | ||
| MPA | C0 (mg l−1) | 2.0 (1.3–8.5) | 2.4 (1.71–6.1) | NS | +0.04 (−1.4, +1.5) |
| Dose-corrected C0 (mg l−1 g−1) | 3.99 (2.5–17.1) | 4.43 (1.8–24.3) | NS | +0.23 (−4.0, +4.4) | |
| Cmax (mg l−1) | 20.1 (10.7–28.5) | 10.6 (6.5–21.3) | 0.0075 | −6.5 (−2.1, −10.9) | |
| Dose-corrected Cmax (mg l−1 g−1) | 40.1 (21.4–57.0) | 19.8 (7.0–42.2) | 0.0028 | −14.9 (−5.8, −24.0) | |
| tmax (h) | 0.5 (0.33–1) | 1.0 (0.33–2) | 0.0289 | +0.39 (+0.03, +0.75) | |
| AUC0−4 (mg h−1 l−1) | 22.4 (13.1–29.8) | 20.4 (13.9–43.0) | NS | +1.67 (−4.1, +7.5) | |
| Dose-corrected AUC0−4 (mg h−1 l−1 g−1) | 44.8 (26.2–59.5) | 38.7 (20.4–99.2) | NS | −0.86 (−14.0, +12.3) | |
| AUC0−12 (mg h−1 l−1) | 26.3 (18.3–55.3) | 30.2 (14.3–62.6) | NS | +0.82 (−11.8, +13.5) | |
| Dose-corrected AUC0−12 (mg h−1 l−1 g−1) | 52.7 (36.6–111) | 57.8 (28.0–125) | NS | −3.31 (−30.2, +23.5) | |
| CL/F (l h−1) | 19.0 (9.0–27.3) | 17.3 (8.0–35.8) | NS | −6.51 (−28.0, +15.0) | |
| CL/F/kg (l h−1 kg−1) | 0.25 (0.12–0.57) | 0.22 (0.09–0.63) | NS | −0.11 (−0.44, +0.21) | |
| MPAG | C0 (mg l−1) | 49.1 (26.5–68.4) | 53.8 (32.2–121) | NS | +11.1 (−73.0, +29.5) |
| AUC0−4 (mg h−1 l−1) | 254 (209–353) | 264 (174–457) | NS | +21.5 (−42.2, +85.1) | |
| Dose-corrected AUC0−4 (mg h−1 l−1 g−1) | 508 (418–705) | 457 (328–1589) | NS | +30.3 (−185, +245) | |
| Cmax (mg l−1) | 72.7 (64.3–102) | 84.7 (45.8–123) | NS | +7.0 (−10.7, +24.7) | |
| tmax (h) | 1.0 (0.5–2) | 2.0 (0.5–4) | 0.0040 | +1.0 (+0.32, +1.70) | |
Data are expressed as median and range.
When gastric emptying of solids was evaluated by the 14C-octanoate breath test, a significant difference between the two groups was found for MPA Cmax but not tmax (Table 3).
Table 3.
Comparison of MPA pharmacokinetic parameters between renal allograft recipients with normal and delayed gastric emptying, as measured with the 14C-octanoate breath test for solids
| 14C-octanoate breath test | |||||
|---|---|---|---|---|---|
| Normal (n = 11) | Delayed (n = 15) | P-value | Mean difference (95% CI) | ||
| MPA | C0 (mg l−1) | 2.3 (1.3–8.5) | 2.27 (1.7–6.09) | NS | −0.09 (−1.5, +1.3) |
| Dose-corrected C0 (mg l−1 g−1) | 4.6 (2.5–17.1) | 3.7 (1.8–24.3) | NS | +0.39 (−3.6, +4.4) | |
| Cmax (mg l−1) | 15.6 (7.6–28.5) | 11.0 (6.5–21.2) | 0.0290 | −5.0 (−0.55, −9.5) | |
| Dose-corrected Cmax (mg l−1 g−1) | 29.4 (15.1–57.0) | 20.5 (7.0–42.4) | NS | −10.2 (−0.62, −19.8) | |
| tmax (h) | 0.5 (0.33–2) | 1.0 (0.33–2) | NS | +0.17 (−0.21, +0.54) | |
| AUC0−4 (mg h−1 l−1) | 19.3 (13.1–43.0) | 20.7 (15.3–35.3) | NS | +1.4 (−4.2, +6.9) | |
| Dose-corrected AUC0−4 (mg h−1 l−1 g−1) | 38.6 (26.2–59.5) | 38.8 (20.4–99.2) | NS | +2.1 (−10.4, +14.6) | |
| AUC0−12 (mg h−1 l−1) | 26.3 (18.3–55.3) | 30.2 (14.3–62.6) | NS | +5.3 (−6.7, +17.2) | |
| Dose-corrected AUC0−12 (mg h−1 l−1 g−1) | 52.7 (36.6–111) | 57.8 (28.0–125) | NS | +7.4 (−18.2, +32.9) | |
| CL/F (l h−1) | 19.0 (9.0–27.3) | 17.3 (8.0–35.8) | NS | +10.2 (−10.0, +30.4) | |
| CL/F/kg (l h−1 kg−1) | 0.25 (0.12–0.57) | 0.22 (0.09–0.63) | NS | +0.15 (−0.15, +0.46) | |
| MPAG | C0 (mg l−1) | 48.4 (26.5–68.4) | 53.8 (32.2–121) | NS | +15.4 (−1.6, +32.5) |
| AUC0−4 (mg h−1 l−1) | 234 (175–353) | 286 (174–457) | NS | +46.5 (−13.6, +107) | |
| Dose-corrected AUC0−4 (mg h−1 l−1 g−1) | 447 (350–705) | 505 (328–1589) | NS | +114 (−88.3, +316) | |
| Cmax (mg l−1) | 71.5 (45.8–102) | 89.3 (49.2–124) | NS | +13.6 (−3.0, +30.3) | |
| tmax (h) | 1.25 (0.5–3) | 2.0 (0.5–4) | NS | +0.36 (−0.40, +1.11) | |
Data are expressed as medians and range.
The gastric emptying half-life and gastric emptying coefficient for fluids correlated significantly with dose-corrected MPA Cmax (R2 = 0.22; P = 0.0158 and R2 = 0.21; P = 0.0207, respectively) but not with MPA tmax (R2 = 0.05 and R2 = 0.02). Similarly, there was a significant weak correlation between the gastric emptying t1/2 and the GEC for solids and dose-corrected MPA Cmax (R2 = 0.17; P = 0.0343 and R2 = 0.22; P = 0.0136). There were no correlations between gastric t1/2 or GEC and MPA(G) AUC0−4 or AUC0−12.
At the time of the study, no patients had hypoalbuminaemia or liver dysfunction. No differences between the study groups were noted for haemoglobin concentration, creatinine clearance, weight or gender that could potentially influence MPA pharmacokinetics or breath test analysis (data not shown). There were no differences in the incidence of acute rejection episodes between the groups (1/11 vs. 5/16; P = 0.1742). However, the power to detect such a difference was low.
Discussion
This study has demonstrated that gastric emptying directly influences the rate of MPA absorption from the gut in renal transplant patients. Delayed gastric emptying of fluids was associated with a 36% decrease in maximum MPA concentration (Cmax) and a significant delay in reaching maximum MPA and MPAG concentrations (based on a retrospective 74% and 83% increase in tmax). When gastric emptying of solids was measured, Cmax was significantly lower in patients with delayed gastric emptying. Statistically significant correlations were found between the gastric emptying coefficient and the gastric emptying half-life of both fluids and solids and dose-corrected MPA Cmax. However, total dose-interval exposure to MPA and to MPAG exposure (AUC0−4) were not affected by the rate of gastric emptying.
The results of the present study confirm previous findings [23] that delayed gastric emptying is frequent after renal transplantation. As delayed gastric emptying was associated with a delay in tmax, it is clear that the use of limited sampling algorithms to calculate total MPA AUC should incorporate not only MPA concentration data in the first hour after dosing, but also later time points. Failure to take account of this could lead to underestimation of the AUC of MPA in patients with delayed gastric emptying. However, as only abbreviated MPA time–concentration profiles were obtained in this study, and total MPA AUC0−12 could only be estimated by the use of predictive algorithms, it was not possible to test this hypothesis. Further studies utilizing 12-h concentration–time profiles are necessary to confirm the influence of gastric emptying on the accuracy of predicted MPA AUC0−12, using different limited sampling strategies.
Our findings corroborate those of Bullingham et al. in patients with rheumatoid arthritis, demonstrating that the AUC0−12 of MPA in fed individuals was equivalent to that in the fasted state, and that MPA tmax was slightly delayed and Cmax fell by 25%, consistent with delayed gastric emptying in the fed state [13]. In addition, data from the current study are in accordance with earlier studies demonstrating delayed MPA tmax in diabetic patients [16, 17]. As MPA is almost completely absorbed [24], an effect of gastric emptying on total MPA exposure would not be expected. In patients with delayed gastric emptying, a dose of MMF will reach the small intestine somewhat later and probably in a less concentrated form, but the extent of MPA absorption remains complete.
The weak correlation observed between gastric emptying parameters and MPA Cmax and tmax prevents the use of gastric emptying rates for predictive purposes. The correlation between the gastric emptying of solids and MPA pharmacokinetics was less pronounced compared with that of fluids. This difference can be explained by the rapid dissolution rate of the MMF tablet formulation in the stomach.
The observation that gastric motility does not influence total MPA exposure is a significant finding, since the latter is an important determinant of the clinical efficacy of the drug [25], whereas MPA Cmax is probably associated with drug-related side-effects [26]. In this small cohort we could not demonstrate a difference in acute rejection rate or the incidence of MPA-related side-effects between patients with and without delayed gastric emptying. However, since gastric emptying was assessed in stable patients, 2 years after transplantation, the incidence of rejection or side-effects was very low.
Our findings suggest that the concomitant use of drugs that enhance gastric motility (e.g. metoclopramide, cisapride, domperidone and erythromycin) could lead to increased maximal MPA plasma concentrations, whereas agents that delay gastric emptying (e.g. opioids, anticholinergics and sympathomimetics) may have the opposite effect [27].
In conclusion, total MPA exposure was not affected by the rate of gastric emptying. Delayed gastric emptying of fluids was associated with a decrease in MPA Cmax and a longer tmax in stable renal allograft recipients on MMF therapy. Data on the effect of gastric emptying rate on these early MPA exposure parameters might be valuable for designing MMF dosing algorithms based on abbreviated sampling strategies. Further studies are warranted to investigate the effect of drugs that influence gastric emptying on MPA pharmacokinetics.
Acknowledgments
We thank the clinical nurses A. Herelixka, H. Wieland and R. Eerdekens for their continuous support and their enduring enthusiasm for clinical research. We thank H. de Loor (Laboratory of Nephrology, University Hospital Gasthuisberg, Leuven, Belgium) for her excellent technical assistance.
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