ORIGINAL ARTICLE. Received March 9, 2009; accepted July 14, 2009.

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1 LIVER TRANSPLANTATION 15: , 2009 ORIGINAL ARTICLE Comparison of Pharmacokinetics of Mycophenolic Acid and Its Metabolites Between Living Donor Liver Transplant Recipients and Deceased Donor Liver Transplant Recipients Shen Baiyong, 1 * Chen Bing, 2 * Zhang Weixia, 2 Mao Huarong, 1 Shen Chuan, 1 Deng Xiaxing, 1 Zhan Xi, 1 and Chen Hao 1 From the 1 Center of Organ Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and 2 Institute of Clinical Pharmacology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Living-donor liver transplantation (LDLT) has been considered an alternative method for treatment of patients with end-stage liver disease. However, the characteristics of pharmacokinetics of mycophenolic acid (MPA) in patients who underwent LDLT were not clear. This study was designed to compare the pharmacokinetics of MPA and its metabolites between LDLT patients and deceased donor liver transplant (DDLT) patients after oral administration of mycophenolate mofetil (MMF). Thirteen patients who underwent LDLT and 14 patients who underwent DDLT were enrolled prospectively. All patients received oral MMF administration (1.0 g, twice daily) in combination with tacrolimus (TAC). The plasma concentrations of MPA, free MPA, glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by high-performance liquid chromatography method. There was a wide variation in various pharmacokinetic parameters of MPA and its metabolites in patients who underwent LDLT and DDLT after oral MMF administration. Although mean MPA area under the plasma concentration time curve for 0-12 hours (AUC 0-12h ) of MPA and MPAG in DDLT patients were higher than those in LDLT patients, there was no significant difference between the two groups. MPA concentration at 6 hours (C 6h ), C 10h,C 12h, and MPA AUC 6-12h were significantly higher in DDLT group than those in LDLT group (P 0.05). Inversely, higher free MPA AUC 0-12h and significant free MPA fraction (P 0.05) in LDLT patients were observed in DDLT patients when compared with DDLT group. AcMPAG concentrations at 4, 8, and 10 hours and AcMPAG AUC 0-12h were significantly higher in the DDLT group (P 0.05). In conclusion, after a fixed oral dose of MMF, DDLT patients had higher enterohepatic recycling contributing to total MPA exposure compared with LDLT patients. The function of glucuronide conjugation in LDLT patients was decreased compared with that in DDLT patients. Higher free MPA AUC 0-12h and a significantly higher fraction of free MPA in LDLT patients suggested that a lower oral dose of MMF may be administered for patients who underwent LDLT. Liver Transpl 15: , AASLD. Received March 9, 2009; accepted July 14, Mycophenolate mofetil (MMF) has been widely used for the prevention of acute rejection in liver transplantation. 1 It was suggested that MMF allows the safe reduction of calcineurin inibitor dose with a low risk of rejection and an improvement in renal function. 2 After oral administration, MMF is rapidly hydrolysed to the active Abbreviations: AcMPAG, acyl glucuronide; AUC, area under the plasma concentration time curve; CL/F, oral clearance; C 0h and C max, predose and maximum (peak) concentrations; MMF, mycophenolate mofetil; MPA, mycophenolic acid; MPAG, glucuronide. *These authors contributed equally to this study. This study was supported by Natural Science Foundation of Shanghai (No: 08ZR ). The authors have no conflicts of interest that are directly relevant to the content of this study. Address reprint requests to Chen Hao, Center of Organ Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai , China. Telephone: 86(0) ; haochendr@yahoo.com.cn; fax: DOI /lt Published online in Wiley InterScience ( American Association for the Study of Liver Diseases.

2 1474 BAIYONG ET AL. product, mycophenolic acid (MPA). 3 Subsequently MPA is extensively metabolized by uridine diphosphate glucuronsyltransferase enzymes in the liver, gut, and kidney to its inactive metabolite, phenyl mycophenolic acid glucuronide (MPAG). 4 MPAG is extensively bound to serum albumin, from which it can displace MPA, and is excreted in the urine and bile 5. A second and less abundant metabolite is the acyl glucuronide (AcMPAG). Unlike MPAG, AcMPAG is pharmacologically active. AcM- PAG plasma concentrations in patients treated with MMF reach an average of 10%-20% at respective MPA concentrations. 6,7 MPA is an acidic compound that is extensively ( 95%) bound to albumin at clinically relevant concentrations. However, free MPA (fmpa), rather than total MPA, is the pharmacologically active form of the drug. 8 It has been confirmed by some investigations that interpatient variability of MPA exposure in LT recipients and also there are few data to provide guidelines for therapeutic drug monitoring after liver transplantation. 9,10 In our previous study, a large interindividual variability of MPA area under the curve (AUC) has been observed in decreased donor liver transplant (DDLT) patients who received a fixed dose of 1 g MMF twice daily. 11 Many patients have decreased total MPA exposure due to low concentrations of albumin and high concentrations of bilirubin. 12 An increased free fraction (decrease in protein binding) can lead to lower total MPA concentrations and relatively unchanged fmpa concentrations by a restrictive clearance mechanism. The study by van Gelder et al. 13 suggested that any investigation of the pharmacokinetics of MMF in liver transplant patients should measure both free and total concentrations. Recently, living donor liver transplantation (LDLT) has been performed worldwide for treatment of patients with end-stage liver disease and for overcoming the serious shortage of deceased donors. Because the LDLT patients receive only about half of normal hepatic volume, the small hepatic volume could affect the pharmacokinetics of immunosuppressive agents In the current study, we evaluated the pharmacokinetics of MPA and its metabolites after oral MMF administration in LDLT patients and in DDLT patients as well. PATIENTS AND METHODS Patients The study design was approved by the independent ethics committee of Ruijin Hospital, and the procedure was described in detail to all patients before admission and informed consent was obtained. Thirteen LDLT patients and fourteen DDLT patients were enrolled prospectively in this study in the Organ Transplantation Center of Ruijin Hospital. Immunosuppressive Protocol Triple immunosuppressive protocol including MMF (Cellcept, Roche), tacrolimus (TAC; Prograf, Astellas), and steroid was used in two groups of patients. One gram of MMF was given within 6 hours before liver transplantation and 1.0 g was administered twice daily after transplant operation. TAC was given 2 hours later than MMF. Trough concentration of TAC was monitored daily. The dose of TAC was adjusted according to the target range of 5-10 ng/ml. Methylprednisolone was injected during the anhepatic period, and dosage was tapered after operation. After 1 week, prednisone was given at 20 mg daily. Basiliximab (Simulect, Novartis) was taken for immune induction therapy. Blood Sampling A set of blood samples was taken respectively in two groups of patients within the second week after transplantation. Blood samples for analysis of MMF concentration were obtained before dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing. All plasma samples were stored at 20 C until analysis. In addition, laboratory tests were also taken at MPA sampling day. MPA Pharmacokinetic Analysis Concentration of MPA, fmpa, MPAG, and AcMPGA were determined using a high-performance liquid chromatography (HPLC) procedure. The accuracy of the HPLC method used in the Institute of Clinical Pharmacology of Ruijin Hospital was ensured by participating in the MPA Proficiency Testing Scheme, provided by the Cardiac and Vascular Sciences Analytic Unit, St. George s Hospital Medical School (London, UK). The HPLC system includes an isocratic pump, a diode array detector, and an automatic sampling system (all components are from Angilent system, Germany). A Zorbax Eclipse XDB C18 column (250 mm 4.6 mm internal diameter, and 5 m pore size) was used to carry out the separation. The mobile phase consisted of 20 mmol/l NaH 2 PO 4 buffer (ph 3.0, adjusted with 20% phosphoric acid) and methanol (45:55, vol/vol), the column temperature was 45 C, and the flow rate was 1.2 ml/minute. The detector wavelength was set at 304 nm. Ethylene diamine tetraacetic acid plasma (100 L) was mixed with 5 L 20% phosphoric acid in an Eppendorf tube. Protein-precipitating reagent (100 L) was added. The tubes were mixed for 20 seconds on a vortex machine and then centrifuged at 13,000 rpm for 10 minutes. Then, 20 L of the clear supernatant was injected into a Waters HPLC system. The MPA, MPAG, and AcMPAG concentrations were calculated with the ratio of the peak areas of these analyses and IS. Another 0.5 ml of supernatant was added to the Vivaspin 500 ultrafiltration devices (Satorius Stedim Biotech), and a molecular weight cutoff of 10 kda was used to generate plasma ultrafiltrate. The devices were centrifuged in an Eppendorf 5804R centrifuge with fixed-angle rotor (Eppendorf Inc., Hamburg, Germany) at 10,000 rpm for 30 minutes at 25 C. Twenty L of ultrafiltrate was injected into a Waters HPLC system with a 2475 fluorescence detector. The fmpa was separated on a Zorbax Eclipse XDB C18 column (250 mm 4.6 mm internal diameter, 5 m pore size) with the mobile phase consist-

3 MYCOPHENOLIC ACID PHARMACOKINETICS IN LIVER TRANSPLANT RECIPIENTS 1475 TABLE 1. Demographics of LDLT Patients and DDLT Patients Characteristic LDLT DDLT Sex (M/F) 11/2 13/1 Age Body weight (kg) Body height (cm) Primary hepatic diseases Hepatitis B viral cirrhosis with hepatocellulor carcinomas 5 3 Hepatitis B viral cirrhosis 3 7 Severe hepatitis B 2 2 Secondary biliary cirrhosis 0 1 Wilson s disease 3 0 Intrahepatic cholestasis after liver transplantation 0 1 TABLE 2. Comparison of Laboratory Tests Between LDLT Group and DDLT Group Parameter LDLT DDLT P Values Red blood count ( 10 9 /L) Hemoglobin (g/l) Hematocrit (%) White blood count ( 10 9 /L) Platelet ( 10 9 /L) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Gamma glutamyl transpeptidase (U/L) Alkaline phosphatase (U/L) Serum albumin (g/l) Serum total bilirubin (mmol/l) Serum creatine (mmol/l) ing of buffer (10 mmol/l Na 2 HPO 4 and 15 mmol/l of Tris boric acid, ph 8.5) and methanol (40:60, vol/vol), with flow rate set at 1.0 ml/minute. The wavelengths of detection were set at 342 nm (excitation) and 425 nm (emission), respectively. Winnolin 4.1 software was adopted to calculate t max, maximum concentration (C max ), AUC 0-12h of MPA, fmpa, MPAG, AcMPAG, area under the moment curve (AUMC), oral clearance (CL/F), and mean residence time (MRT) of MPA by using noncompartmental analysis. Full 12-hour AUC was determined according to the linear trapezoidal rule. Fraction of fmpa was calculated by dividing fmpa concentrations by total MPA concentrations. The parentto-metabolite concentration ratios were calculated by dividing MPA concentrations by MPAG and AcMPAG concentrations. The differences in the MPA and glucuronide molecular weights were used to correct the ratios. Because the molecular weight of MPAG and AcMPAG are identical, no correction was applied to calculate MPAG to AcMPAG concentration ratio. Statistical Analysis SPSS 13.0 software for Windows was used for statistical analysis. Data were expressed as the mean standard deviations and a P value below 0.05 was considered to be statistically significant. Grouped data were compared by the Mann-Whitney U test. RESULTS The demographics of these two groups of patients, including age, body weight, body height, and primary liver disease, are shown in Table 1. On the sampling day, the laboratory test results were compared between the two groups. There was no significant difference in the majority of laboratory parameters including serum albumin, total bilirubin, and creatine levels except for white blood counts (Table 2). Figures 1-4 represent concentration time profiles of MPA and related compounds. There was a wide variation in various pharmacokinetic parameters of MPA and its metabolites after oral MMF administration in patients who had undergone LDLT and DDLT. Total MPA concentrations were significantly higher at 6, 10, and 12 hours after dose in the DDLT group (Fig. 1). The pharmacokinetic properties of MPA and fmpa are shown in Table 3. Higher CL/F (P 0.073) and significantly lower MPA AUMC (P 0.05) were evident in the LDLT group as compared to the DDLT group. Although, on average, patients who had undergone DDLT had higher MPA AUC 0-12h than patients who had undergone LDLT, MPA AUC 0-12h values were not significantly different between the two groups (P 0.099). However, MPA AUC 6-12h, which is the indicator of enterohepatic recirculation of MPA, was significantly lower in the LDLT group than that in the DDLT group (P 0.05).

4 1476 BAIYONG ET AL. Figure 1. Comparison of the mean plasma concentration time profile of MPA between the LDLT group and the DDLT group. *P < Figure 2. Comparison of mean plasma concentration time profile of free MPA between the LDLT group and the DDLT group. Inversely, on average, patients in the DDLT group had lower free MPA AUC 0-12h than patients in the LDLT group, and the values were not significantly different as well (P 0.159). There was no significantly difference in T max,c max of MPA and fmpa between the two groups (Table 3). And the concentrations of free MPA during the 12-hour interval were not significantly different between the two groups (Fig. 2). However, the percentage of free MPA, which is the indicator of extent of plasma protein binding, was significantly higher in LDLT patients than that in DDLT patients (P 0.05). DISCUSSION This is the first study to compare the pharmacokinetics of MPA and its metabolites after oral MMF administration between patients who had undergone LDLT and DDLT. Furthermore, we are the first to have measured fmpa concentrations in LDLT and DDLT pa-

5 MYCOPHENOLIC ACID PHARMACOKINETICS IN LIVER TRANSPLANT RECIPIENTS 1477 Figure 3. Comparison of mean plasma concentration time profile of MPAG between the LDLT group and the DDLT group. Figure 4. Comparison of mean plasma concentration time profile of AcMPAG between the the LDLT group and the DDLT group. * P < 0.05 tients. Some observations are interesting and noteworthy. Large interindividual variation in MPA pharmacokinetics after oral administration has been well-recognized in liver transplant recipients. 9,11,17 In this study, such a phenomenon still remained not only in DDLT patients but also in LDLT patients. By applying an identical oral dosage regimen, the plasma MPA AUC 0-12h was higher in DDLT patients compared with LDLT patients, although a significant difference was not reached. In addition, MPA C 6h,C 10h,C 12h, and MPA AUC 6-12h were significantly higher in the DDLT group than those in the LDLT group (P 0.05). These results showed that more MPAG was excreted into the

6 1478 BAIYONG ET AL. TABLE 3. Comparison of MPA and Free MPA Pharmacokinetics Between the LDLT Group and the DDLT Group LDLT DDLT P Value MPA T max (hours) C 0h (mg/l) C max (mg/l) AUMC (mg.hour 2 /L) MRT (hours) CL/F (L/hour) AUC 6-12h (mg.hour/l) AUC 0-12h (mg.hour/l) free MPA T max (hour) C 0h ( g/l) C max ( g/l) AUC 0-12h ( g.hour/l) Fraction free (%) Abbreviations: AUMC, area under moment curve; MRT, mean residence time; MPA, mycophenolic acid; AUC, area under curve. TABLE 4. Comparison of MPA Metabolites Pharmacokinetics Between the LDLT Group and the DDLT Group LDLT DDLT P Value MPAG T max (hours) C 0h (mg/l) C max (mg/l) AUC 0-12h (mg.hour/l) AcMPAG T max (hours) C 0h (mg/l) C max (mg/l) AUC 0-12h (mg.hour/l) MPAG to AcMPAG concentration ratio MPA to MPAG concentration ratio MPA to AcMPAG concentration ratio Abbreviations: MPAG, mycophenolic acid glucoronide, AcMPAG, acyl mycophenolic acid glucoranide; MPA, mycophenolic acid; AUC, area under curve. bile and was deconjugated back to MPA leading to more MPA reabsorbed in the colon in the DDLT group. Shaw et al. 18 suggested that the occurrence of a secondary MPA concentration peak anywhere from 4-12 hours following the morning dose of MMF is thought to be the result of enterohepatic recycling. It was evident that enterohepatic recycling contributes more to MPA exposure in the DDLT group compared with the LDLT group. However, CL/F of MPA was higher in the LDLT group than that in the DDLT group. These results were opposite to the observations by Jain et al., 16 in which, after intravenous MMF administration, MPA AUC 0-12h was significantly higher and CL/F was significantly lower in the LDLT patients compared with the DDLT patients. Two reasons could explain such differences. First, the pathway of drug administration was different. Second, blood samples were obtained on postoperative day 2 or day 3 in the study by Jain et al. In our study, blood samples were drawn on the second postoperative week. In an experiment in partially hepatectomized rats, Tian et al. 19 reported that the hepatic intrinsic clearance of MPA was decreased to 52% and 51% of that in control rats at the 24th hour and the 6th day, respectively, but recovered to normal level by day 14. The total body clearance of MPA was reduced at the 24th hour but recovered by day 6. We thought that the total body clearance of MPA was recovered after the second week both in LDLT and DDLT patients. Some factors including body weight, serum albumin concentration, renal function, and immunosuppressant cotherapy have a significant influence on CL/F. 5 In population pharmacokinetic studies in renal transplant recipients, MPA CL/F in adults ranges from 11.9 to 25.4 L/hour under the combination of tacrolimus therapy. 20 In the current study, these factors

7 MYCOPHENOLIC ACID PHARMACOKINETICS IN LIVER TRANSPLANT RECIPIENTS 1479 were similar in DDLT and LDLT patients. Therefore, the reason for higher CL/F in the LDLT group was not clear and perhaps was related to the hepatic regeneration. Another important observation in this study was that the fmpa fraction was significantly higher in the LDLT group than that in the DDLT group (P 0.05). The fmpa AUC 0-12h was also higher in patients with LDLT, although they were not significantly different. Total MPA CL/F appears to increase in proportion to the increased free fraction, with a reduction in total MPA AUC. 21 Because the total MPA concentration appears to be reduced due to increased CL/F, the net result may vary little in the absolute free concentration of MPA. MPA is extensively bound to albumin at clinically relevant concentrations. The degree of protein binding has a significant intraindividual and interindividual variation due to factors such as serum albumin concentration, renal function, and coadministration of drugs which may compete with and/or displace MPA from its protein binding sites. 8,22 Free MPA concentration seems to be constant in patients with preserved renal function. In stable transplant patients, the fmpa fraction ranges from 1%-3%. 22 The factors leading to increased fmpa concentration included patients with poor renal function, liver disease, hypoalbuminemia, and severe infection. 23,24 Shaw et al. 25 suggested that an increase of two-fold to three-fold in fmpa concentration was shown in patients with renal failure. Because the conditions before and after operation were not different in LDLT group and DDLT group in the current study, the reason for increased free MPA AUC and fraction fmpa was directly related to increased CL/F. Nowak et al. 8 has shown that fmpa, rather than total MPA, is the pharmacologically active form of the drug. As such, it has been suggested that measurement of fmpa is more relevant to therapeutic outcomes when compared to total MPA concentration in liver transplantation. 8,13 In patients with impaired renal or hepatic function or hypoalbuminaemia, free drug measurement could be valuable in further interpretation of MPA exposure. After oral administration of MMF, glucuronidation of MPA to MPAG and AcMPAG in LDLT patients was somewhat inefficient compared with that in DDLT patients. The MPAG concentrations were higher in DDLT patients than those in LDLT recipients at all the sampling time points. These results were consistent with the observations in the study by intravenous infusion of MMF. 16 Tian et al. 26 reported that the function of glucuronide conjugation was impaired after partial hepatectomy in rats and was recovered completely within 2 weeks with hepatic regeneration. The activity of glucuronide-conjugating enzymes was decreased due to reduced liver mass during the hepatic regeneration process. These observations suggested that the ability of clearance of MPA has decreased in LDLT patients during the early period after operation. Higher MPAG concentrations have been reported in patients with renal dysfunction 6 and MPAG clearance is also dependent on renal function in liver transplant recipients. 27 Because renal function in DDLT patients decreased compared with LDLT patients (lower serum creatine level), the higher MPAG concentrations may be due to the impaired elimination of MPAG in DDLT patients. In addition, a higher serum level of total bilirubin was observed in DDLT patients. Hyperbilirubinemia may be a factor influencing the pharmacokinetics of MPA. However, higher bilirubin concentrations seemed not to lead to the reduction of hepatic glucuronidation. The results from the study by Parker et al. 28 suggested that hepatic cirrhosis did not significantly affect plasma protein binding of MPA or MPAG, and reduced hepatic glucuronidation of MPA may be compensated by enhanced renal glucuronidation. In another study by Jain et al. 2, it was suggested that T-tube clamping did not affect the pharmacokinetics of MPA or MPAG over one dosing interval. We thought that the impact of hyperbilirubinemia on hepatic glucuronidation of MPA has not been understood definitely. In conclusion, after a fixed oral dose of MMF, lower MPA AUC 0-12h and significant lower MPA AUC 6-12h were observed in LDLT patients. DDLT patients had higher enterohepatic recycling contribution to total MPA exposure. Inversely, higher free MPA AUC and significant higher fraction free MPA were observed in LDLT patients. As free MPA is the pharmacologically active form, lower oral dose of MMF may be administered for LDLT patients. 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