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PHARMACOKINETICS AND PHARMACODYNAMICS |
From the Department of Pharmaceutical Sciences and Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania (Dr Pisupati, Dr Burckart, Ms Zuckerman, Dr Venkataramanan) and the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Jain, Dr Hamad, Dr Fung).
Address for reprints: Raman Venkataramanan, PhD, FCP, 718 Salk Hall, University of Pittsburgh, Pittsburgh, PA 15261.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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.05) with time from 9.1 ± 7.2 µg/mL (<1 week) to 36.7 ± 15.6 µg/mL (1 month). The area under the plasma concentration versus time curve of mycophenolic acid also increased significantly with time, from 50.8 ± 42.1 µg•h/mL to 118.0 ± 57.6 µg•h/mL (P .05). The plasma protein binding of mycophenolic acid increased from 92% to 98%, and the apparent oral clearance [CL/F] decreased from 32.9 ± 21.4 L/h during the first study period to 9.0 ± 4.4 L/h (P .05) during the third study period. The apparent intrinsic clearance of mycophenolic acid did not change significantly over time. The ratio of the area under the curve of mycophenolic acid glucluronide to mycophenolic acid in plasma decreased with time (25.5 ± 21.2 vs 8.0 ± 3.3) but did not reach statistical significance. The increased binding of mycophenolic acid to plasma proteins with time after transplantation appeared to contribute to the intraindividual variation, whereas differences in the ability of the liver to metabolize mycophenolic acid between patients appear to contribute to the large interindividual variation in the pharmacokinetics of mycophenolic acid. The observations in this study support the concept of measuring the unbound concentration of mycophenolic acid to optimize immunosuppressive drug therapy with mycophenolic acid.
Key Words: Mycophenolic acid • mycophenolate mofetil • immunosuppressive drugs • pharmacokinetics • mycophenolic acid glucuronide • interindividual variations • intraindividual variations
Large interindividual and intraindividual variability in the pharmacokinetics of several drugs has been reported in organ transplant patients.5-8 This variability may be due to changes in absorption, distribution, metabolism, and elimination of drugs in this patient population. Factors that contribute to these changes include (1) changes in gut and biliary function; (2) changes in the plasma protein binding; (3) changes in the functional capacity of the liver to metabolize drugs; (4) changes in the circulating levels of endogenous mediators such as endotoxin, cytokines, and nitric oxide, which could affect drug metabolism; (5) changes in the biliary transport of compounds; and (6) changes in renal function due to the concurrent use of nephrotoxic drugs such as tacrolimus and cyclosporine.
MPA is extensively bound (97%-98%) to human serum albumin.9 Studies in renal transplant patients with renal dysfunction have also shown an increase in the unbound fraction of MPA due to changes in albumin concentrations.10,11 Albumin concentrations are normally low in patients with liver disease. Subsequent to a liver transplantation (LTx), albumin concentrations increase toward normal values as the new transplanted liver synthesizes albumin.5,12,13 Changes in albumin concentrations and a simultaneous reduction in plasma bilirubin concentration are expected to increase the plasma protein binding of mycophenolic acid in liver transplant patients. Based on the pharmacokinetics of MPA in renal transplant patients and the physiological changes observed in liver transplant patients, we hypothesized that the plasma protein binding of MPA will be low in LTx during the early posttransplant period but will increase with time after transplantation. We also hypothesized that there will be differences in the rate of conjugation of MPA within and between LTx patients, leading to altered clearance of MPA. In the present study, we evaluated the time-dependent changes in the pharmacokinetics of MPA in LTx patients during 3 different time periods.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Subjects
Male and female patients, between the ages of 31 and 60 years, who were receiving MMF as part of their postoperative immunosuppressive therapy participated in this study. All the patients were on tacrolimus and steroid therapy. Concomitant use of other medications generally prescribed to these patients included antacids, antibacterial agents, and antiviral agents. Patients were excluded if they were pregnant or were receiving drugs known to inhibit or induce (other than steroids) hepatic drug-metabolizing enzymes during the study period. Food and water intake was not restricted during the study periods.
Study Design
The pharmacokinetics of MPA was evaluated on 3 separate occasions (1 week, >1 week and 2 weeks, and 
3 weeks and 6 weeks) after LTx. The patients were studied while in the intensive care unit (ICU) within the hospital or at the outpatient clinic. Blood (2.5 mL) samples were collected in Vacutainers with EDTA as anticoagulant immediately before and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after the regular oral dose of MMF (0.5-1 g bid). Blood samples were centrifuged at room temperature, and the plasma was separated and frozen at -70°C and analyzed for MPA and MPAG by high-pressure liquid chromatography (HPLC). Urine was collected for the entire 12-hour study period. Urine was aliquotted and frozen at -70°C until analysis of MPA and MPAG by HPLC. Biochemical parameters indicative of liver and renal function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, and albumin; blood urea nitrogen and serum creatinine) were measured as part of postoperative care in these patients.
Laboratory Analysis
The HPLC assay procedures for measuring MPA and MPAG were developed in our laboratory and reported earlier.14 The concentration of MPA in plasma and urine was measured after a solid-phase extraction (Seppak 1-mL C18 cartridges, Waters Corp, Milford, Mass). To 250 µL of the sample, 50 µL of internal standard (diazepam, 15 ng/mL) and 1 mL of 0.1N HCl were added, and the sample was vortexed. The sample was then passed through a C18 Sep-pak cartridge (Waters Corp) previously conditioned with 2 mL methanol and 10 mL water. The components of interest were eluted with 2 mL methanol. The methanolic extract was dried under nitrogen. The dried sample was reconstituted in 125 µL of 60:40 water and acetonitrile. Then, 100 µL of this solution was injected onto the HPLC column. A HPLC column (LC-18, Pico-tag, Waters-5µ; 3.9 mm i.d.; 300 mm long) maintained at 50°C was used in an isocratic mode (1.2 mL/min) with a mobile phase of acidified H2O (pH 4.5-5.0)/acetonitrile (59:41). Mycophenolic acid was monitored at 254 nm. The retention times for MPA and the internal standard were 5.6 and 10.7 minutes, respectively. The standard curve was prepared in plasma at the following concentrations: 0, 0.25, 0.5, 1.0, 2.5, 5.0, 10.0, and 25.0 µg/mL. The coefficient of variation of this assay was 4.8% to 8.6% (0.25-25 µg/mL). For the measurement of MPAG in the plasma and urine, 20 µL of plasma or urine (diluted 20 times with deionized water), 50 µL of internal standard (0.15 µg/mL phenolphthalein glucuronide), and 50 µL of acetonitrile were mixed, vortexed, and centrifuged (13,000 rpm) for 3 minutes. To 25 µL of supernatant, 25 µL of a mixture of mobile phase was added, and 30 µL of this solution was injected onto the HPLC column. A Hypersil BDS C-18 column (5 µ; 4.6 mm i.d.; 250 mm long; Alltech Association Inc, Deerfield, Ill,) was used, with a mobile phase composition of acidified water (591 µL of 85% of orthophosphoric acid in 1 L of DI water)/acetonitrile (74:26) in an isocratic mode at a flow rate of 1.1 mL/min. Mycophenolic acid glucuronide and the phenolphthalein glucuronide were monitored at 254 nm. The retention times for MPAG and phenolphthalein glucuronide were 10.8 and 12.2 minutes, respectively. The standard curve for MPAG was prepared in plasma at the following concentrations: 0, 2.5, 5.0, 12.5, 25.0, 50, 100, and 200 µg/mL. Samples with concentration values that exceeded 200 µg/mL were diluted and reanalyzed. The coefficient of variation was 3.7% at 25 µg/mL and 2.7% at 100 µg/mL.
The plasma protein binding of MPA was determined by ultrafiltration using Amicon filters (1 mL capacity, 30,000 molecular weight cutoff; Millipore Corporation, Bedford, Mass). Four to 5 plasma samples representing approximately every other time point in the pharmacokinetic study were pooled, and MPA in methanol (<5%) was added to achieve an approximate total concentration of 25 to 30 µg/mL. The total plasma concentration of MPA was measured in 50 µL of this sample. The rest of the sample was subjected to ultrafiltration using a Millipore ultrafiltrate device with centrifugation of the sample at 3000 rpm for approximately 1 hour at room temperature. The concentration of MPA in the filtrate and in the plasma was measured by HPLC as described above. The unbound fraction of MPA was calculated by the following equation:
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The percent unbound was calculated as fu x 100. All the samples were analyzed in duplicate. Earlier studies have shown the unbound fraction of MPA to be constant up to at least 50 µg/mL of MPA.
Pharmacokinetic and Statistical Analysis
Area under the plasma concentration-time curve (AUC0-12h), apparent total oral clearance (CL/F), peak concentration (Cmax), and time to peak concentration (tmax) of MPA in plasma were computed by standard noncompartmental methods with WinNonlin (Standard edition, version 1.5). The apparent intrinsic clearance (CLint) was calculated as (CL/F)/fu because MPA is a low-clearance drug.15,16
The relationship between various pharmacokinetic parameters and biochemical indices was examined by simple linear regression analysis. Repeated-measures ANOVA (SAS, release 8.01) was used to compare the various calculated parameters between the 3 study periods. Results were considered to be statistically significant at P .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The percent unbound MPA ranged from 0.3% to 7.5% during the first study period. The mean percent unbound decreased from 4.3% during the first study period to 1.9% during the third study period (Figure 1, Table II), indicating increased binding of MPA to plasma proteins with time after transplantation.
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Figures 2 and 3 show the plasma concentration versus time profile of MPA and MPAG in a patient after liver transplantation. A secondary peak in MPA was seen between 4 and 6 hours after MMF administration in 4 of 10 LTx patients during the third study period, indicative of possible enterohepatic circulation. The pharmacokinetic parameters of MPA and MPAG are summarized in Table II. The time to reach maximum concentration (tmax) did not change significantly (1.8 ± 1.2 vs 1.3 ± 0.7 h) between the first and the third study periods. The Cmax increased approximately 3-fold (9.1 ± 7.2 vs 36.7 ± 15.6 µg/mL) with time. Similarly, the AUC increased significantly (approximately 2.5-fold) from 50.8 ± 42.1 to 118 ± 57.6 µg•h/mL. The apparent oral clearance of total MPA (CL/F) decreased from 32.9 ± 21.4 L/h during the first study period to 9.0 ± 4.4 L/h during the third study period. The apparent CLint of MPA varied among the patients during each study period, as indicated by a large standard deviation (see Figure 4). However, the CLint of MPA was not significantly different at different study periods (Table II). The within-patient variability in the CLint of MPA was less than 20%.
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There was a significant correlation between the percent unbound MPA and the apparent oral clearance of the total drug. A significant correlation (r = 0.88) was observed between the unbound fraction and the plasma albumin concentrations, as determined by the following relationship:
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where Ka is the affinity constant, fup is the fraction of the total number of binding sites unoccupied, and Pt is the concentration of plasma albumin.
The relationship between the AUC0-12 of MPA and various biochemical indices was also examined. A moderate correlation was observed between the biochemical indices of bilirubin (r2 = 0.4), albumin (r2 = 0.4), ALT (r2 = 0.4), AST (r2 = 0.5), and MPA AUC0-12. However, no correlation was observed between MPA AUC and serum creatinine concentrations.
The Cmax and tmax for MPAG did not change over time. The AUC of MPAG was several folds higher than the AUC of MPA and did not change over time (Table II). The calculated ratio of the AUC of MPAG/MPA decreased from the first to the third study periods, but this did not achieve statistical significance. Poor correlations were observed between MPAG AUC or MPAG/MPA AUC ratio and serum creatinine. The percentage of the dose excreted in the urine over a dosing interval as MPAG was 36% during the first study period and 17% during the third study period.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Several reports have indicated interpatient variability with immunosuppressive agents such as tacrolimus and cyclosporine. The variability in the kinetics of cyclosporine has been related to factors such as changes in absorption, variability in liver or renal function, age, food intake, and concurrent drug therapy.5,19-21 Other studies have suggested that the wide interpatient variation in the doses needed to achieve an appropriate blood concentration of tacrolimus could be due to the variation in activity of drug-metabolizing enzymes (CYP3A) or drug transporter.7,22,23
The pharmacokinetics of MMF has been previously evaluated in renal and pancreas transplant patients. These studies have demonstrated wide variations in the kinetics of MPA when a fixed dose of MMF was administered to the patients.15,16,24-31 However, limited information is available on the pharmacokinetics of MPA in liver transplant patients.14,32-34
In the present study, we evaluated the pharmacokinetics of MPA in LTx patients on 3 separate occasions in the immediate posttransplant period. In liver transplant patients, mycophenolate mofetil was rapidly absorbed after oral administration and readily converted to MPA. This is similar to what is observed in healthy volunteers and in kidney transplant patients.15,16,25,26,28,29,35 MMF concentrations have been reported to be below detection limits in these patients within 1 hour after dosing. In our study, a 4-fold increase in the peak concentration (Cmax) of MPA was observed between the first and the third study periods. This could be due to improved absorption of MPA over time. However, it was not possible to ascertain whether changes in absorption contributed to the changes observed in this study, as an intravenous formulation was not available at the time of the study.
MPA is highly bound to albumin in plasma.9 In vitro studies have shown that the inhibition of IMPDH is dependent on the unbound concentration of MPA.9 The concentration of albumin increases and the concentration of bilirubin decreases after liver transplantation. Our results indicate that plasma protein binding of MPA increased as the concentration of albumin increased and the concentration of bilirubin decreased with time in these subjects. Increased binding leads to decreased unbound fraction. This is typical of acidic drugs that show decreased binding in renal impairment, liver disease, and posttransplantation.5,13,36 There was a 2.5-fold difference in the mean unbound fraction (fu) between the first study period and the third study period. This could have contributed to the observed differences in the pharmacokinetics of MPA between studies and within patients. The unbound fraction is similar to but more variable than what is reported in other transplant patient populations.10,11,37
The total AUC0-12 of MPA increased nearly 2.5-fold with time. The increase in total AUC correlated well with the decrease in percent unbound MPA. The total clearance (CL) of MPA decreased with increased binding, and this was significant between the first and the third study periods. The clearance of MPA similarly correlated with an increase in percent unbound MPA. Because MPA is a low-clearance drug, a decrease in the unbound fraction due to increased albumin, decreased bilirubin concentration, and other factors will decrease the clearance and increase total AUC. These results also agree with the isolated liver perfusion rat (IPRL) study, in which changes in the albumin concentrations produced drop changes in the clearance of MPA.38 Time-dependent changes in the AUC of MPA have also been reported in kidney transplant patients.30
To identify other possible determinants of changes in MPA AUC, the relationships between biochemical indices such as ALT, AST, bilirubin, albumin, and MPA AUC were evaluated. AUC0-12 was moderately correlated to covariates such as ALT, AST, and bilirubin. No correlation was observed between MPA AUC0-12 and serum creatinine. However, the serum creatinine was fairly normal in our study population. We have previously observed a positive correlation between the MPAG/MPA AUC ratio and serum creatinine concentrations in patients with varying degrees of renal function. In a study evaluating the pharmacokinetics of MPA in adult kidney transplant recipients, AUC0-12 was positively predicted by both serum creatinine and serum albumin but not by time after transplantation, body weight, or trough concentrations.28 In a pediatric liver transplant population, the trough MPA correlated well (r2 = 0.65) with the AUC of MPA.39 This is similar to our observation (r2 = 0.6) in this study.
There was no change in the intrinsic clearance (CLint) of MPA within the patients in this study. The lack of a significant change in the intrinsic clearance indicates that the inherent ability of the liver to metabolize and eliminate MPA did not change significantly over time in this study population. However, large variability was observed between patients. This large variability between patients could be due to differences in the amount of glucuronide-conjugating enzyme content in the liver or in the content of cosubstrate UDPGA in the liver or the effect of cytokines or nitric oxide on the metabolism of MPA. An understanding of the importance and contribution of these factors requires future studies.
It is known that MPA is predominantly converted to MPAG, a glucuronide conjugate.15,16 Very high plasma concentrations of MPAG in comparison to MPA were observed in all the patients studied. There was a 2.5-fold difference in the ratio of the AUC of MPAG to MPA from the first study to the third study. The AUC of MPAG did not change with time, whereas the MPA AUC increased with time.
Higher trough plasma concentrations and AUCs of MPA have been reported in kidney transplant patients receiving tacrolimus in comparison to those on cyclosporine.27 In our study, it was not possible to directly confirm this observation because all the patients were receiving tacrolimus. It was not possible to ascertain whether there were any changes in the enterohepatic recycling, which could have contributed to the changes seen in the kinetics of MPA over time.
In summary, we have observed time-dependent changes in the fu, AUC, and CL of MPA in liver transplant patients treated with MMF and tacrolimus. Our observations are consistent with published information in kidney transplant patients treated with cyclosporine and MMF. Our data also indicate large interpatient variability in the CLint of MPA in liver transplant patients. The 2 factors that contributed to the overall variability in the pharmacokinetics of MPA are changes in plasma protein binding and changes in intrinsic clearance. Changes in plasma protein binding contributed to the intraindividual variability, whereas differences in plasma protein binding and differences in intrinsic clearance appear to have contributed to the interindividual variations. The large variability in the pharmacokinetics of MPA seen in different patients indicates the need for therapeutic monitoring of MPA in transplant patients. Because MPA is a low-clearance drug and is slightly bound to plasma proteins, free or unbound drug may be a better measure of drug exposure than the total drug. Future clinical studies that evaluate the unbound MPA concentration and the clinical outcomes are necessary.
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FOOTNOTES |
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Submitted for publication April 21, 2004; Revised version accepted August 16, 2004.
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