霉酚酸在肝移植病人体内的药代动力学研究

目的研究免疫抑制剂霉酚酸酯(MMF)的活性代谢物霉酚酸(MPA)在肝移植病人体内的药代动力学。方法38例肝移植病人(男30例，女8例)术后早期按推荐剂量(每次1.0 g，每天两次)口服MMF达稳态，在给予一个早晨的剂量(1.0 g)后，在1个给药间隔内，于给药前及给药后不同时间点采血，用HPLC法测定MPA血药浓度，用3P97软件计算药代动力学参数。结果病人口服MMF后，血浆MPA浓度在给药后0.5～6.0 h内达峰值，部分病人在给药后4～12 h出现第2个小峰，血药峰浓度(C_max)和药-时曲线下面积(AUC_{0-12 h})均值分别为(12±7) μg·mL^-1和(44±16) μg·h·mL^-1，病人个体间存在较大差异。结论MPA在肝移植病人体内的药代动力学存在较大个体差异，提示在临床用药时需要监测MPA血药浓度，进行个体化给药。     

Intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid in liver transplant patients

The authors evaluated the intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid after oral administration of mycophenolate mofetil in 10 liver transplant patients. Mycophenolic acid and its metabolite, mycophenolic acid glucuronide, were measured in plasma and urine by high-pressure liquid chromatography. The plasma protein binding of mycophenolic acid was determined by ultrafiltration. The maximum concentration of mycophenolic acid in plasma increased significantly (P < or = .05) with time from 9.1 +/- 7.2 microg/mL (<1 week) to 36.7 +/- 15.6 microg/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 microg x h/mL to 118.0 +/- 57.6 microg x h/mL (P < or = .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 < or = .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.     

Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.     

Pharmacokinetics and pharmacodynamics of mycophenolic acid after enteric-coated mycophenolate versus mycophenolate mofetil in patients with progressive IgA nephritis

Mycophenolic acid can be administered orally using mycophenolate mofetil or enteric-coated mycophenolate. In renal transplant patients on immunosuppressant combination therapy, the overall mycophenolic acid exposure after oral dosing with mycophenolate mofetil and enteric-coated mycophenolate is similar. This study compared pharmacokinetics and pharmacodynamics of mycophenolic acid after equivalent doses of enteric-coated mycophenolate (360 mg twice daily) or mycophenolate mofetil (500 mg twice daily) in 7 patients with progressive IgA nephritis (glomerular filtration rate 20-35 mL/min) using a randomized crossover design. The pharmacokinetics of mycophenolic acid concentrations and pharmacodynamics (using inosine 5'-monophosphate dehydrogenase activity as a bio-marker) were sequentially monitored for 12 hours. After enteric-coated mycophenolate treatment, the mycophenolic acid peak concentration (Cmax = 12.8 vs 6.0 microg/mL, P < .05) and the overall exposure were significantly higher (AUC = 60.9 vs 40.7 microg.h/mL, P < .05), and the apparent clearance was significantly lower (CL/F = 7.9 vs 10.7 L/h, P < .05) as compared to that after mycophenolate mofetil. Paradoxically, inosine 5'-monophosphate dehydrogenase activity was not significantly different. In conclusion, the steady-state mycophenolic acid exposure was higher during treatment with enteric-coated mycophenolate as compared to mycophenolate mofetil, which might be explained by more extensive enterohepatic recycling of mycophenolic acid after administration of enteric-coated mycophenolate, whereas inosine 5'-monophosphate dehydrogenase suppression was not different.     

Pharmacokinetic study of mycophenolic acid in Korean kidney transplant patients

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and 18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60% +/- 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration-time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, C(max), and t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC.     

Automated determination of free mycophenolic acid and its glucuronide in plasma from renal allograft recipients

Mycophenolic acid, the active moiety of mycophenolate mofetil, inhibits the enzyme inosine monophosphate dehydrogenase. The main metabolite, mycophenolic acid glucuronide, has no immunosuppressive effect. Reported protein bindings are 97% for mycophenolic acid and 82% for mycophenolic acid glucuronide. Considerable intraindividual and interindividual variability in mycophenolic acid pharmacokinetics has been observed. Data on the variability of mycophenolic acid free fraction in plasma are sparse but may be relevant when discussing whether therapeutic drug monitoring of this drug is warranted. The authors describe a fully automated method for the determination of free concentrations by dialysis across a membrane followed by concentration of the dialysate on a trace enrichment column and liquid chromatography. Total concentrations are measured by protein precipitation and direct injection on the trace enrichment column. Plasma concentrations as low as 6 ng/mL free mycophenolic acid and 1 microg/mL free mycophenolic acid glucuronide can be measured with between-day coefficient of variation less than 15% and 6%, respectively. Stability testing confirmed that plasma samples could be stored for 14 days at 4 degrees C or -20 degrees C and at room temperature for approximately 12 hours without significant changes in free concentrations. Predose total and free concentrations of mycophenolic acid and mycophenolic acid glucuronide were determined in 27 samples from stable renal allograft recipients treated with mycophenolate mofetil, cyclosporin, and steroids. Total concentrations ranged from 0.57 to 16.2 microg/mL mycophenolic acid and 36 to 199 microg/mL mycophenolic acid glucuronide. Free concentrations ranged from 13 to 210 ng/mL mycophenolic acid and 8 to 58 microg/mL mycophenolic acid glucuronide. The method presented here has been successfully applied to measure free mycophenolic acid and free mycophenolic acid glucuronide in clinical samples. Further investigations may provide important data to support the identification of principles and target ranges for the monitoring of mycophenolic acid in the immunosuppressive therapy of organ transplant recipients.     

Drug interaction between mycophenolate mofetil and tacrolimus detectable within therapeutic mycophenolic acid monitoring in renal transplant patients.

The possible pharmacokinetic interaction between the new immunosuppressive mycophenolate mofetil (MMF) and tacrolimus (TAC), respectively, was assessed by comparing routinely estimated mycophenolic acid (MPA) plasma trough levels of 15 consecutive renal transplant patients receiving MMF in combination with methylprednisolone (MEP) and cyclosporin A (CSA, 10 patients) or in combination with MEP and tacrolimus (TAC, 5 patients). Coadministration of TAC instead of CSA resulted in a significant increase of mean MPA plasma trough levels [3.4 +/- 1.3 microg/mL (n = 22) versus 1.87 +/- 1.1 microg/mL (n = 57); p < 0.001], despite lower MMF doses [1.5 +/- 0.5 g/d versus 1.7 +/- 0.3 g/d (not statistically significant)]. This elevation in MPA levels is possibly caused by an interaction between MMF and TAC and could lead to a recommendation to monitor MPA plasma levels with appropriate dose adjustment.     

Higher mycophenolate dose requirements in children undergoing hematopoietic cell transplant (HCT)

Little is known about dosing of mycophenolate mofetil in pediatric hematopoietic cell transplant recipients; therefore, dosing strategies using other settings have been extended to this population. The authors studied pharmacokinetics in 19 children (median 17 months) undergoing myeloablative hematopoietic cell transplant and receiving prophylactic mycophenolate and cyclosporine. All subjects except 2 received mycophenolate 15 mg/kg intravenously every 8 hours. The median (range) total mycophenolic acid area under the concentration-time curve (AUC)(0-8) was 12.6 mcg.h/mL (4.9-49.2), and unbound mycophenolic acid AUC(0-8) was 0.274 mcg.h/mL (0.037-1.4). Total and unbound mycophenolic acid trough concentrations were 0.27 (0.03-2.9) and 0.005 (0-0.034) mcg/mL, respectively. Mycophenolic acid trough concentrations were not good surrogates for overall exposure (AUC(0-8)), r(2) < or = 0.55. Mycophenolate dose requirements are higher in pediatric hematopoietic cell transplant recipients relative to pediatric organ transplant recipients. Children undergoing hematopoietic cell transplant should receive a mycophenolate mofetil dose of at least 15 mg/kg intravenously every 8 hours when used in combination with cyclosporine to achieve systemic concentrations near those proposed to be therapeutic in the adult hematopoietic cell transplant population.     

Early pharmacokinetics of low dosage mycophenolate exposure in Thai kidney transplant recipients

Background The effects of mycophenolic acid exposure in the early period after transplantation on clinical outcomes have been reported; however, mycophenolic acid exposure in the early period after transplantation in Asian kidney transplant recipients who receive 1.5 g/d mycophenolate mofetil has never been investigated. Objective To determine mycophenolic acid exposure on day 3 post-transplantation in kidney transplant recipiens who receive 1.5 g/d mycophenolate mofetil. The effects of the reduced renal function on mycophenolic acid area under the concentration–time curve (AUC) and the achievement of the target AUC on the incidence of biopsy proven acute rejection during the first month post-transplantation were also evaluated. Setting A university hospital Method Blood samples and 24-h urine were collected on day 3 post-transplantation. Main outcome measures The mycophenolic acid AUC was calculated by linear trapezoidal rule and compared with the target of 45 mg*h/L. Results Of 42 Thai kidney transplant recipiens, the mean mycophenolic acid AUC of 45.1 mg*h/L (SD 14.7) was comparable to the AUC target (P?=?0.962). Significant differences of the mycophenolic acid AUC were observed between patients with urine output of?<?2400 mL and those with urine output?≥?2400 mL (35.3?±?6.6 and 47.4?±?15.2, respectively; P?=?0.002), and between patients with 24-h measured CrCl?<?25 mL/min and those with CrCl?≥?25 mL/min (38.0 (29.0, 42.2) and 49.2?±?14.0, respectively; P?=?0.017). Proportions of overall biopsy proven acute rejection among patients with mycophenolic acid AUC of?<?45 and?≥?45 mg*h/L were comparable (20.0% and 23.5%, respectively; P?=?1.000). Conclusions After the starting dosage of 1.5 g/d mycophenolate mofetil, the mean mycophenolic acid AUC on day 3 post-kidney transplantation is comparable with the target of 45 mg*h/L. Severely reduced renal function significantly influences mycophenolic acid exposure.

     

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant

AIMS: The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients. METHODS: Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant. RESULTS: Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4). CONCLUSIONS: The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.     

Highly variable mycophenolate mofetil bioavailability following nonmyeloablative hematopoietic cell transplantation

This study determined the oral bioavailability of mycophenolic acid, the active metabolite of mycophenolate mofetil, in patients undergoing nonmyeloablative hematopoietic cell transplantation. Eighteen adults receiving a preparative regimen containing fludarabine, cyclophosphamide, and total body irradiation were studied. Immune suppression consisted of cyclosporine and mycophenolate 1 g twice daily. Pharmacokinetic variability was high after intravenous and oral dosing. Intravenous dosing resulted in a median area under the curve (AUC) of 28.3 microg x h/mL (range, 9.96-70.4) and an oral AUC of 16.7 microg x h/mL (range, 9.38-35.3). Cmax after intravenous and oral dosing was 12.18 and 5.29 microg/mL, respectively. The median oral bioavailability was 72.3% (20.5%-172%), with 8-fold variability. Five patients (28%) had an oral bioavailability < or = 50%. At time of oral pharmacokinetics, 15 patients (83%) had an AUC(0-12) < 30 microg x h/mL. The initial oral dose should be at least 25% greater than the intravenous dose with follow-up assessment of plasma concentrations.     

The occurrence of diarrhea not related to the pharmacokinetics of MPA and its metabolites in liver transplant patients

Purpose  

Mycophenolate mofetil (MMF) is a pro-drug that is hydrolyzed to release mycophenolic acid (MPA). Subsequently MPA is extensively metabolized to phenyl mycophenolic acid glucuronide (MPAG) and MPA acyl glucuronide (AcMPAG). It was presumed that the closest association is between plasma AcMPAG concentrations and the incidence of diarrhea. This study aimed to investigate the correlation between pharmacokinetics of MPA, MPAG, and AcMPAG and diarrhea in liver transplant recipients on MMF with tacrolimus.     

Absorption characteristics of EC-MPS--an enteric-coated formulation of mycophenolic sodium

Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine. OBJECTIVE: Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine. METHODS: Study 1: The mean MPA AUC(0-t) was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 microg x h/ml). Mean absolute bioavailability was 0.71 +/- 0.21 (SD). Study 2: The AUC(0-t) and C(max) for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC(0-infinity) and C(max) for MPA glucuronide were proportional to dose administered. RESULTS AND CONCLUSIONS: In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 - 2,160 mg with no serious adverse events reported.     

Pharmacokinetics and protein binding of mycophenolic acid in stable lung transplant recipients

Mycophenolate mofetil (MMF) use is increasing in solid organ transplantation. Mycophenolic acid (MPA), the active metabolite of MMF, is highly protein bound and only free MPA is pharmacologically active. The average MPA free fraction in healthy adult individuals, stable renal transplant recipients, and heart transplant recipients is approximately 2 to 3%. However, no data are currently available on MPA protein binding in stable lung transplant recipients and little is known regarding MPA's pharmacokinetic characteristics after lung transplantation. The purpose of this study was to characterize the pharmacokinetic profile and protein binding of MPA in this patient population. Seven patients were entered into the study. On administration of a steady-state morning MMF dose, blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 8, 9, 10, and 12 hours post-dose. Total MPA concentrations were measured by a validated HPLC method with UV detection and followed by ultrafiltration of pooled samples for free MPA concentrations. Area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), trough concentration (Cmin), free fraction (f), and free MPA AUC were calculated by traditional pharmacokinetic methods. Patient characteristics included; 3 males and 4 females, an average of 4.4 years post-lung transplant (range, 0.3-11.5 yr), mean (+/- SD) age of 50 +/- 10 years and weight 69 +/- 20 kg. Mean albumin concentration was 37 +/- 3 g/L and serum creatinine was 142 +/- 49 micromol/L. All patients were on cyclosporine and prednisone. MMF dosage ranged from 1 to 3 g daily (35.5 +/- 14.1 mg/kg/d; range, 15.2-60.0 mg/kg/d). Mean (+/- SD) AUC was 45.78 +/- 18.35 microg.h/mL (range, 16.56-74.22 microg.h/mL), Cmax was 17.37 +/- 7.69 microg/mL (range, 4.92-26.63 microg/mL), Tmax was 1.2 +/- 0.4 hours (range, 1.0-2.0 h), Cmin was 3.12 +/- 1.41 microg/mL (range, 1.47-4.82 microg/mL), f was 2.90 +/- 0.56% (range, 2.00-3.40%), and free MPA AUC was 1.29 +/- 0.50 microg.h/mL (range, 0.54-1.88 microg.h/mL). This is the first study to determine these pharmacokinetic characteristics of MPA in the lung transplant population. Further studies should focus on identification of MMF dosing strategies that optimize immunosuppressive efficacy and minimize toxicity in lung allograft recipients.     

Influence of cyclosporine on the serum concentration and biliary excretion of mycophenolic acid and 7-O-mycophenolic acid glucuronide

The authors have investigated whether cyclosporine decreases the serum concentration of mycophenolic acid, the active principle of the immunosuppressant mycophenolate mofetil, and increases that of the inactive metabolite 7-O-mycophenolic acid glucuronide by reducing their enterohepatic recirculation. Rats were treated daily with methylcellulose (1.66 mL/kg PO) plus 0.9% NaCl (6 mL/kg IP), mycophenolate mofetil (20 mg/kg PO) plus 0.9% NaCl (6 mL/kg IP), methylcellulose (1.66 mL/kg PO) plus cyclosporine (5 mg/kg IP), and mycophenolate mofetil (20 mg/kg PO) plus cyclosporine (5 mg/kg IP). After 14 days a bile fistula was installed to measure the biliary excretion of the immunosuppressants and their metabolites. After 90 minutes blood was taken to determine their concentrations in blood or serum by HPLC. Cyclosporine significantly decreased the serum concentration of mycophenolic acid by 39% and increased, not significantly, that of 7-O-mycophenolic acid glucuronide by 53%. The biliary excretion of 7-O-mycophenolic acid glucuronide was significantly reduced by cyclosporine by 57%, whereas that of mycophenolic acid was not affected. Mycophenolate mofetil did not show a significant effect on either the blood concentration or the biliary excretion of cyclosporine and its metabolites AM1, AM9, AM1c, and AM4N. Cyclosporine significantly decreased the serum concentration of active mycophenolate acid and increased, not significantly, the serum concentration of inactive 7-O-mycophenolic acid glucuronide, presumably by reducing the biliary excretion of this inactive metabolite.     

霉酚酸在肝移植受者的药代动力学与药效学相关性研究

目的研究肝移植受者早期口服霉酚酸(免疫抑制剂)药代动力学与药效学的相关性。方法20例肝移植受者口服霉酚酸酯前、后,用酶增强免疫法测定患者血浆霉酚酸浓度。服药前(0h)及服药后1,2h,用患者血清处理人急性淋巴细胞白血病T淋巴(CEM)细胞,检测CEM细胞的增殖情况。结果口服霉酚酸酯前,CEM细胞增殖率显著高于服药后1,2h(P<0.05);服药后1,2h霉酚酸浓度与相应的CEM细胞增殖率呈负相关(P<0.05)。结论肝移植受者口服霉酚酸酯后,血清对CEM细胞的增殖产生显著抑制作用,其作用和霉酚酸浓度呈显著负相关。     

A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients

AIM: To compare the pharmacokinetics of mycophenolic acid when given with either ciclosporin or sirolimus, and investigate in vitro the potential effect of ciclosporin, sirolimus, tacrolimus and everolimus on mycophenolic acid metabolism. METHODS: In renal transplant patients given mycophenolate mofetil in combination with ciclosporin (n = 19) or sirolimus (n = 12), concentration-time profiles of mycophenolic acid, mycophenolic-acid-phenyl-glucuronide, mycophenolic-acid-acyl-glucuronide and mycophenolic-acid-phenyl-glucoside were determined at one month post-transplant. The effect of immunosuppressive drugs on mycophenolic acid glucuronidation and glycosylation was investigated in vitro using human liver microsomes. RESULTS: The mean mycophenolic acid AUC(0-9 h) in the sirolimus group was 44.9 mg h(-1) L(-1) (95% CI: 34.7-55.1), vs. 30.5 mg h(-1) L(-1) (95% CI: 25.4-35.6) in the ciclosporin group, corresponding to 1.5-fold dose-normalized difference (95% CI: 1.1-1.9; P < 0.05). In addition, the metabolite/mycophenolic acid AUC(0-9 h) ratios were significantly higher in patients cotreated with ciclosporin than with sirolimus, giving values of 1.8-fold (95% CI: 1.3-2.3; P = 0.0009), 2.6-fold (95% CI: 2.0-3.3; P < 0.0001) and 4.3-fold (95% CI: 2.6-6.0; P = 0.0016) for mycophenolic-acid-phenyl-glucuronide, mycophenolic-acid-acyl-glucuronide and mycophenolic-acid-phenyl-glucoside, respectively. In vitro, none of the immunosuppressive drugs tested inhibited mycophenolic acid metabolism. CONCLUSION: Patients taking mycophenolate mofetil and sirolimus experience a higher exposure to mycophenolic acid and a lower exposure to mycophenolic acid metabolites than those being treated with mycophenolate mofetil and ciclosporin. This interaction is probably not caused by inhibition of mycophenolic acid glucuronidation or glycosylation, but is more likely to be due to the influence of ciclosporin on the excretion of mycophenolic acid metabolites into bile.     

Investigation on pharmacokinetics of mycophenolic acid in Chinese adult renal transplant patients

AIMS: To characterize the pharmacokinetics of mycophenolic acid (MPA) in Chinese renal transplant patients. METHODS: Thirty-one renal transplant patients (17 male, 14 female) receiving mycophenolate mofetil (MMF) 1.0 g twice daily were included in this study. A pharmacokinetic study was performed during an interval in dosing after steady state had been reached within 2 months after transplantation. The plasma MPA concentration were measured by high-performance liquid chromatography (HPLC) at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software. SAS software was used for statistical analysis. Multiple linear regression analysis was used to determine limited sampling approaches. RESULTS: The mean peak plasma concentration (C(max)) and area under the concentration-time curve (AUC(0-12)) were 19.67 +/- 8.21 microg ml(-1) and 52.16 +/- 12.50 microg h ml(-1), but there was large variability in these pharmacokinetic parameters. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that each of the concentrations at 0.5, 1, 4 and 10 h was positively correlated with AUC (r = 0.60, P = 0.0004; r = 0.60, P = 0.0003; r = 0.61, P = 0.0003; r = 0.64, P = 0.0001, respectively). The combined use of these four samples explained over 90% of the variance in the total (nine-point) AUC(0-12). A formula was obtained for the assessment of MPA AUC based on four samples: MPA AUC = 12.61 + 0.37 x C(0.5) + 0.49 x C(1) + 3.22 x C(4) + 8.17 x C(10). CONCLUSIONS: Chinese renal transplant patients had higher median AUCs than caucasians and African-Americans. As in other studies, there was large interindividual variability. A limited four-point AUC was in good agreement with the 12-h AUC and provided the basis of a predictive formula.     

Enteric-coated mycophenolate sodium for transplant immunosuppression.

PURPOSE: The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, monitoring, and dosage and administration of enteric-coated (EC) mycophenolate sodium are reviewed. SUMMARY: EC mycophenolate sodium is the EC salt form of mycophenolic acid (MPA), the active component of the pro-drug, mycophenolate mofetil. EC mycophenolate sodium was developed to reduce the upper-gastrointestinal (GI) effects of mycophenolate mofetil. Unlike oral mycophenolate mofetil, which releases MPA in the stomach, EC mycophenolate sodium releases MPA in the small intestine. The absolute bioavailability of EC mycophenolate sodium is 72%. MPA undergoes hepatic metabolism by glucuronyl transferase to the inactive mycophenolic acid glucuronide (MPAG), the predominant metabolite. The majority of an administered dose of EC mycophenolate sodium is found as MPAG in the urine. The mean terminal half-life of MPA ranges from 8 to 16 hours. EC mycophenolate sodium and mycophenolate mofetil have equivalent mechanisms of action and drug interaction profiles. Thus far, EC mycophenolate sodium has demonstrated similar efficacy and safety to mycophenolate mofetil in two Phase III clinical trials of adult renal transplant recipients. One study demonstrated improved health-related quality of life in patients switched from mycophenolate mofetil to EC mycophenolate sodium. Ongoing Phase IV studies are trying to further determine advantages of the EC product. CONCLUSION: EC mycophenolate sodium is a safe and effective immunosuppressive agent approved for use in the prevention of acute rejection after renal transplantation. It offers an excellent addition to the current armamentarium of immunosuppressive drugs for transplant immunosuppression.     

Pharmacokinetics of mycophenolic acid and determination of area under the curve by abbreviated sampling strategy in Chinese liver transplant recipients

OBJECTIVES: This study aimed to: (i) define the clinical pharmacokinetics of mycophenolic acid (MPA) in Chinese liver transplant recipients; and (ii) develop a regression model best fitted for the prediction of MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) by abbreviated sampling strategy. METHODS: Forty liver transplant patients received mycophenolate mofetil 1g as a single dose twice daily in combination with tacrolimus. MPA concentrations were determined by high-performance liquid chromatography before dose (C(0)) and at 0.5 (C(0.5)), 1 (C(1)), 1.5 (C(1.5)), 2 (C(2)), 4 (C(4)), 6 (C(6)), 8 (C(8)), 10 (C(10)) and 12 (C(12)) hours after administration on days 7 and 14. A total of 72 pharmacokinetic profiles were obtained. MPA AUC(12) was calculated with 3P97 software. The trough concentrations (C(0)) of tacrolimus and hepatic function were also measured simultaneously. Multiple linear regression analysis was used to establish the models for estimated MPA AUC(12). The agreement between predicted MPA AUC(12) and observed MPA AUC(12) was investigated by Bland-Altman analysis. RESULTS: The pattern of MPA concentrations during the 12-hour interval on day 7 was very similar to that on day 14. In the total of 72 profiles, the mean maximum plasma concentration (C(max)) and time to reach C(max) (t(max)) were 9.79 +/- 5.26 mg/L and 1.43 +/- 0.78 hours, respectively. The mean MPA AUC(12) was 46.50 +/- 17.42 mg . h/L (range 17.99-98.73 mg . h/L). Correlation between MPA C(0) and MPA AUC(12) was poor (r(2) = 0.300, p = 0.0001). The best model for prediction of MPA AUC(12) was by using 1, 2, 6 and 8 hour timepoint MPA concentrations (r(2) = 0.921, p = 0.0001). The regression equation for estimated MPA AUC(12) was 5.503 + 0.919 . C(1) + 1.871 . C(2) + 3.176 . C(6) + 3.664 . C(8).This model had minimal mean prediction error (1.24 +/- 11.19%) and minimal mean absolute prediction error (8.24 +/- 7.61%). Sixty-three of 72 (88%) estimated MPA AUC(12) were within 15% of MPA AUC(12). Bland-Altman analysis also revealed the best agreement of this model compared with the others and a mean error of +/-9.89 mg . h/mL. CONCLUSION: This study showed the wide variability in MPA AUC(12) in Chinese liver transplant recipients. Single timepoint MPA concentration during the 12-hour dosing interval cannot reflect MPA AUC(12). MPA AUC(12) could be predicted accurately using 1, 2, 6 and 8 hour timepoint MPA concentrations by abbreviated sampling strategy.