Whole Blood Tacrolimus Concentrations Research Articles

Specificity of a Circulating Antibody That Interferes With a Widely Used Tacrolimus Immunoassay

Accurate measurement of whole-blood tacrolimus concentration is essential for achieving therapeutic immunosuppression and minimizing toxicity in renal transplant recipients. Falsely elevated or decreased values may trigger unnecessary dose adjustments. We identified a falsely elevated whole-blood tacrolimus immunoassay result in a renal transplant patient. Twelve hours after the patient received his first dose, the blood concentration was 24.4 ng/mL using the Siemens Dimension RxL immunoassay. Immunoabsorption studies showed that the cause of the interference was an endogenous antibody present in the patient's plasma that recognized a unique epitope present on the antibody-enzyme (beta-galactosidase) conjugate used in the Siemens tacrolimus immunoassay but not on the antibody or beta-galactosidase alone. This report adds to the growing knowledge base of endogenous antibody interferences in diagnostic immunoassays. To our knowledge, this is the first such report of a falsely elevated tacrolimus concentration due to recognition of an epitope present only on the monoclonal antibody-enzyme conjugate.

High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation

We hypothesized that a high within-patient variability in clearance of tacrolimus and mycophenolate mofetil (MMF) would put patients at risk for periods of over- or underimmunosuppression and would thus lead to long-term chronic allograft nephropathy and graft loss after transplantation. From 297 patients transplanted between 1 January 2000 and 31 December 2004, the within-patient variability in clearance was calculated from tacrolimus whole-blood concentrations and mycophenolic acid (MPA) plasma concentrations drawn between 6 and 12 months post-transplantation. As a primary outcome, a composite end point consisting of graft loss, biopsy-proven chronic allograft nephropathy and 'doubling in plasma creatinine concentration in the period between t = 12 months post-transplantation and last follow-up' was used. In the study population of 297 patients, 34 patients reached the primary end point of graft failure. The within-patient variability in the clearance of tacrolimus and three other covariates are significant risk factors for reaching the composite end point of failure [P-values for intraindividual tacrolimus variability = 0.003, biopsy-proven acute rejection (BPAR) = 0.003, recipient age at transplantation = 0.005]. The mean tacrolimus concentration for controls [7.4 (+/- 2.9) ng/mL] and for failures [6.9 (+/- 2.5) ng/mL] was similar. Within-patient variability in the clearance of MPA was not related to reaching the composite end point of failure. This study shows a significant relationship between the high within-patient variability in the clearance of tacrolimus, but not for MPA, and long-term graft failure.

Falsely elevated whole-blood tacrolimus concentrations in a kidney-transplant patient: potential hazards

Tacrolimus-based immunosuppression is the most frequently prescribed immunosuppression for kidney-transplant (KT) patients. Because tacrolimus has a narrow therapeutic window, drug monitoring is mandatory. Of the many methods used to assess whole-blood trough levels, antibody-conjugated magnetic immunoassay (ACMIA) is popular because, compared with microparticle enzyme-linked immunoassays (MEIA), there is no need to pretreat samples, thus reducing time taken by the laboratory technician. Herein, we report on a KT tacrolimus-treated patient who experienced falsely elevated whole-blood tacrolimus concentrations after using the ACMIA method. ACMIA gave trough levels of 24 ng/ml, whereas the actual trough level, when measured by enzyme-multiplied immunoassay technique (EMIT) and high-performance liquid chromatography coupled with mass spectrometry (LC-MS/MS), was nil. After a workup we only found one factor that might have caused the elevated concentration: positive anti-double stranded DNA autoantibodies. We conclude that, when ACMIA produces surprisingly high tacrolimus concentrations in organ-transplant patients, these should be reassessed immediately using either LC-MS/MS or another immunoassay in order to eliminate falsely elevated results.

Falsely Elevated Whole Blood Tacrolimus Concentrations due to Interference in an Affinity Column-Mediated Immunoassay Method on Xpand Dimension

The whole blood concentration of tacrolimus is required for therapeutic drug monitoring of this immunosuppressive drug. Abnormal tacrolimus levels affect its efficacy or toxicity, leading to changes in its dosage. Here, we report analytical interference in the affinity column-mediated immunoassay tacrolimus method on the Xpand autoanalyzer in a kidney transplant human immunodeficiency virus-infected patient. Tacrolimus concentrations obtained by affinity column-mediated immunoassay are 3- to 7-fold higher than measurements with the enzyme multiplied immunoassay technique assay. The cause of this interference remains unknown. However, it would be necessary to identify this type of interference to measure tacrolimus concentration with another method to avoid analytical error, which may lead to a poor clinical outcome.

Is the Affinity Column–Mediated Immunoassay Method Suitable as an Alternative to the Microparticle Enzyme Immunoassay Method as a Blood Tacrolimus Assay?

Background Tacrolimus is a potent immunosuppressive drug used in organ transplantation. Because of its substantial toxic effects, narrow therapeutic index, and interindividual pharmacokinetic variability, therapeutic drug monitoring of whole-blood tacrolimus concentrations has been recommended. We investigated the comparability of the results of 2 immunoassay systems, affinity column–mediated immunoassay (ACMIA) and microparticle enzyme immunoassay (MEIA), comparing differences in the tacrolimus concentrations measured by the 2 methods in relation to the hematologic and biochemical values of hepatic and renal functions. Methods A total of 154 samples from kidney or liver transplant recipients were subjected to Dimension RxL HM with a tacrolimus Flex reagent cartilage for the ACMIA method and IMx tacrolimus II for the MEIA method. Results Tacrolimus concentrations measured by the ACMIA method (n = 154) closely correlated with those measured by the MEIA method ( r = 0.84). The Bland-Altman plot using concentration differences between the 2 methods and the average of the 2 methods showed no specific trends. The tacrolimus levels determined by both the MEIA method and the ACMIA method were not influenced by hematocrit levels, but the difference between the 2 methods (ACMIA − MEIA) tended to be larger in low hematocrit samples ( P < .001). Conclusion The ACMIA method used for a tacrolimus assay is precise and has advantages, including the lack of a required pretreatment procedure. Furthermore, it is only slightly influenced by the hematologic or biochemical status of the samples.

Cloned Enzyme Donor Immunoassay Tacrolimus Assay Compared With High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Microparticle Enzyme Immunoassay in Liver and Renal Transplant Recipients

The immunosuppressant drug tacrolimus has a narrow therapeutic index and is subject to a large variation in individual bioavailability and clearance. With its narrow therapeutic index, therapeutic drug monitoring is standard clinical practice in the management of transplant recipients. In this study, we report the evaluation of the cloned enzyme donor immunoassay (CEDIA) for the determination of whole-blood tacrolimus concentrations compared with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and microparticle enzyme immunoassay (MEIA) using samples obtained from liver (n = 100) and renal (n = 88) transplant recipients. Linear regression analysis showed a relationship of CEDIA = 1.24 HPLC-MS/MS -0.18 (r = 0.81). The mean bias (+/-SEM) for all patients when compared with HPLC-MS/MS was 22.2% (+/-2.1%). The precision of the CEDIA method for all samples showed a root mean square error of 3.1 microg/L. Liver transplant recipient samples showed a mean (+/-SEM) bias compared with HPLC-MS/MS of 12.5% (+/-1.6%). The precision of the CEDIA method for these samples showed a root mean square error of 1.5 microg/L. The data suggest that in the renal transplant group, the CEDIA and MEIA methods have a bias of 33.3% and 20.1%, respectively, compared with HPLC-MS/MS. The CEDIA tacrolimus immunoassay has been shown to be a rapid method for the determination of whole-blood tacrolimus concentrations and may be considered when HPLC-MS/MS is not available. When used in the clinical setting with other parameters, it would be a useful adjunct in the management of liver transplant recipients, but a significant bias in renal transplant patients needs to be further investigated.

Estimation of minimum whole-blood tacrolimus concentration for therapeutic drug monitoring with plasma prednisolone concentration: A retrospective cohort study in Japanese kidney transplant recipients

Background: In immunosuppressive therapy administered after organ transplantation, therapeutic drug monitoring (TDM) of tacrolimus must be performed frequently because of the large variation in its pharmacokinetic properties and a progressive decrease in dose requirements. An indicator for estimating the target minimum whole-blood tacrolimus concentration (C min TAC) would be useful to minimize the number of blood samplings required for tacrolimus TDM. Objectives: The primary objective of this study was to investigate whether plasma prednisolone concentration, postoperative days (POD) and AUC 0 to 9 hours before transplantation (AUC 0–9int) are useful indicators of tacrolimus TDM. The secondary objective was to determine the usefulness of blood tacrolimus concentration as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head, an adverse event that has been associated with the use of prednisolone in vivo. Methods: This open-label, nonrandomized, retrospective study was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Data from 43 male and 22 female patients (mean age, 38 years [range, 9–64 years]) who received a living-related kidney transplant from 2001 to 2004 were included. Multiple blood samplings were performed to determine AUC 0–9int, AUC 0 to 9 hours after drug administration and after transplantation (AUC 0–9), C min TAC, C max, and T max after transplantation. The correlations between each parameter were determined. The correlation between POD and the changes in tacrolimus bioavailability was investigated using the indicator, defined as the tacrolimus dose required to maintain the target (10–15 ng/mL) C min TAC (dose/C 10–15). Correlations between dose/C 10–15 and AUC 0–9int (3 AUC 0–9int groups, defined as follows: low, medium, and high [<93, ≧93−≤152, and ≧152 ng·h/mL, respectively]) were determined. Correlations between mean C min values of prednisolone at a dose of 40 mg on PODs 4 to 11 (C min PSL40) and C min TAC, or AUC 0–9int were determined. A subanalysis was used to determine the relationship between dose/C 10–15 and the prevalence of nontraumatic, glucocorticoid-induced necrosis of the femoral head. Results: C min TAC was found to be significantly correlated with AUC 0–9int ( r=0.554; P<0.001) and C min PSL40 ( r=0.336; P<0.001). In the low-AUC 0–9int group, dose/C 10–15 was higher than that of the other groups ( P<0.001). AUC 0–9int was significantly correlated with C min PSL40 ( r=0.445; P<0.001)). Dose/C 10–15 in the patient group that had necrosis of the femoral head was lower than that of the group without necrosis (n=6; P<0.01). Conclusions: The results of this small, retrospective study suggest that C min PSL40, AUC 0–9int, and POD were significant predictors of C min TAC. These parameters were found to be a useful indicator of tacrolimus TDM in these Japanese transplant recipients. Our results also suggest that dose/C 10–15 and AUC 0–9int might be useful indicators for estimating the risk for nontraumatic, steroid-induced necrosis of the femoral head. ( Curr Ther Res Clin Exp. 2006;67: 103–117) Copyright © 2006 Excerpta Medica, Inc.

Relationship between MDR1 gene polymorphism and blood concentration of tacrolimus in renal transplant patients

To investigate the relationship between MDR1 exon 21 and exon 26 polymorphism and whole blood concentration of tacrolimus (FK506) in renal transplant patients. Blood samples were collected from 86 renal transplant patients who received FK506 peri-operationally. PCR-RELP was used to determine the MDR1 genotype. The patients were divided into 3 subgroups for every position: GG, GT, and TT in exon 21; and CC, CT, and TT in exon 26. Three, six, and twelve months after the transplantation ELISA was used to measure the whole blood concentration of FK506. The FK506 concentrations standardized by dosage and body weight (FK506 concentration per dose/kg) were compared among the 3 subgroups within the MDR1 exon 21 and exon 26 groups. Of the 86 patients 26 (30.2%), 35 (40.7%), and 25 (29.1%) were carriers of GG, GT, and TT in exon 21, and 26 (30.2%), 35 (40.7%), and 23 (26.8%) were carriers of CC, CT, and TT in exon 26. MDR1 exon 26 C3435T was in significant linkage disequilibrium with MDR1 exon 21 G2677T. Three, six, and twelve months after the transplantation a significant correlation between the whole blood FK506 concentration per dose/day and MDR1 exon 21 and exon 26 genotypes. For exon 21 there were significant differences among the 3 subgroups (all P < 0.01). The ratio for the patients with GG was remarkably lower than that of those with GT and TT, and the ratio with GT was also lower than the patients with TT (P < 0.05). For exon 26, there was also a significant difference among the 3 subgroups (all P < 0.01). The ratio for the patients with CC was remarkably lower than those of the patients with CT and TT, and the ratio of CT was also lower than that of TT (P < 0.05). The MDR1 gene polymorphism is correlated with the whole blood concentration of FK506. To obtain the similar blood concentration of FK506, the patients with GG and CC should take the drug at a higher dose than those with Ct and TT.

Safety of tacrolimus, an immunosuppressive agent, in the treatment of rheumatoid arthritis in elderly patients

To prospectively evaluate the safety of tacrolimus in active rheumatoid arthritis (RA) in elderly patients with insufficient response to disease-modifying antirheumatic drugs (DMARDs). Fifty-seven patients aged > or =65 yr with RA for > or =6 months were enrolled in an open-label, non-controlled study. All DMARDs were discontinued and tacrolimus was administered orally once daily after the evening meal for 28 weeks. Tacrolimus, initiated at 1.5 mg/day, was increased to 3 mg/day after 6 weeks if no abnormal changes developed. Existing NSAID and oral corticosteroid (< or =7.5 mg/day prednisolone equivalent) therapy could be continued during the study. Safety was evaluated as clinical symptoms, abnormal changes in laboratory values and the development of infection. Treatment response was determined using the American College of Rheumatology (ACR) criteria for improvement. Whole blood concentrations of tacrolimus 12 h after administration were measured by high-performance liquid chromatography and tandem mass spectrometry. Clinical adverse events developed in 25 patients (46.3%). Abnormal changes in laboratory values occurred in 25 patients (46.3%). Ten patients (18.5%) developed infection. An ACR20 response was achieved by 50.0% of efficacy-evaluable patients and ACR20 success rates (the proportion of patients achieving ACR20 response and completing the study) was 46.3%. The ACR50 response rate was 18.5% of evaluable patients. Mean blood concentration of tacrolimus was 3.3 and 5.3 ng/ml in patients receiving 1.5 and 3.0 mg daily, respectively. No relationship between its concentration and adverse reactions was observed. In elderly patients with insufficient response to DMARD therapy, tacrolimus at 1.5-3.0 mg/day is safe and well-tolerated and provides clinical benefit.

Treatment of acute tacrolimus whole‐blood elevation with phenobarbital in the pediatric liver transplant recipient

The toxicities associated with the chronic use of tacrolimus are well described in the literature; however, little is known about the management during an acute overdose. Phenobarbital is a long-acting barbiturate metabolized in the liver by the cytochrome p450 3a4 system. It is known to enhance the rate of metabolism of itself and the clearance of drugs metabolized by p450 3a4. Because tacrolimus is a substrate of this particular isoenzyme, phenobarbital can be considered a potential option when rapid decreases in tacrolimus whole-blood levels are desired. We hereby report our experience using intravenous phenobarbital in the management of two infants with acute elevations in their tacrolimus whole-blood concentration following liver transplantation. Phenobarbital, through its up-regulation of hepatic cytochrome p450 system increases the elimination of whole-blood tacrolimus concentration in acute overdose situations.

Concomitant Clotrimazole Therapy More Than Doubles the Relative Oral Bioavailability of Tacrolimus

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.

Change in Oral Absorption of Tacrolimus in a Liver Transplant Recipient After Reversal of Jejunoileal Bypass: Case Report

Introduction Jejunoileal bypass (JIB) was, at one time, a popular surgical technique for the treatment of morbid obesity. However, this operation was also associated with major complications. Consequently, many such procedures were eventually reversed. One of the most serious of these complications was liver failure. For those patients who developed cirrhosis, liver transplantation was one therapeutic alternative. Tacrolimus is one of the primary immunosuppressive agents used in liver transplantation. It is effective to prevent acute rejection episodes, but shows a narrow therapeutic index and can cause nephrotoxicity and neurotoxicity. This report describes the change in tacrolimus absorption that was observed after JIB reversal in a 57-year-old female liver transplant recipient. Results Prior to JIB reversal, the mean tacrolimus dose was 7 mg twice daily with a whole-blood tacrolimus concentration ranging from 5.2 to 6.4 ng/mL. There was no appreciable peak in tacrolimus concentration, and the area under the concentration-time curve (AUC) was 10.9 ng/mL/h. After reversal, the daily tacrolimus dose was decreased to 5 mg twice daily, with a now-discernable peak concentration at 3 hours postdose. Furthermore, the AUC increased 90% to 20.7 ng/mL/h. Conclusion After JIB reversal, the patient showed higher systemic levels of tacrolimus and required lower steady-state doses. It is therefore imperative that such patients be monitored closely to avoid tacrolimus-related toxicity.

Effects of some hematological parameters on whole blood tacrolimus concentration measured by two immunoassay-based analytical methods

Objectives: Tacrolimus (FK506) is a potent immunosuppressive drug used for prevention of rejection following transplantation. Several methods including immunoassays have been used for monitoring tacrolimus levels. The purpose of the present study was to compare the effects of various hematological parameters on whole blood tacrolimus concentrations which were measured with two different analytical methods, namely the microparticle enzyme immunoassay (MEIA II) and enzyme multiplied immunoassay technique (EMIT). Design and methods: The effects of hematological variables, namely hematocrit (Htc), hemoglobin (Hb), red blood cell (RBC), mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), red cell distribution width (RDW) and platelet (PLT) counts on tacrolimus concentrations ( n = 2430 measurements) measured with EMIT ( n = 1171) and MEIA II ( n = 1259) methods in whole blood samples from kidney or liver or combined kidney-pancreas transplant patients ( n = 162) during a 2-year post-transplantation period were compared. Results: The whole blood tacrolimus concentrations measured with MEIA II method were affected much more significantly by hematological parameters than those measured with EMIT method. In MEIA II method, RDW ( r = 0.479, P < 0.01) showed a stronger correlation with tacrolimus concentration than Htc ( r = −0.239, P < 0.01) in all patients. A negative significant correlation ( r = −0.468, P < 0.01) was also observed between the Htc and tacrolimus concentration in patients with Htc values ≤25% in MEIA II method. Conclusions: The results of the present study suggest that EMIT method might be preferred to MEIA II in determination of whole blood tacrolimus concentrations in anemic transplant patients. For better therapeutic drug monitoring, physicians should be aware of these assay differences. Evaluation of hematologic factors that affect the whole blood concentrations of tacrolimus may be helpful in deciding the dosage of this drug.

Sampling Times for Monitoring Tacrolimus in Stable Adult Liver Transplant Recipients

The aim of this study was to determine the most informative sampling time(s) providing a precise prediction of tacrolimus area under the concentration-time curve (AUC). Fifty-four concentration-time profiles of tacrolimus from 31 adult liver transplant recipients were analyzed. Each profile contained 5 tacrolimus whole-blood concentrations (predose and 1, 2, 4, and 6 or 8 hours postdose), measured using liquid chromatography-tandem mass spectrometry. The concentration at 6 hours was interpolated for each profile, and 54 values of AUC(0-6) were calculated using the trapezoidal rule. The best sampling times were then determined using limited sampling strategies and sensitivity analysis. Linear mixed-effects modeling was performed to estimate regression coefficients of equations incorporating each concentration-time point (C0, C1, C2, C4, interpolated C5, and interpolated C6) as a predictor of AUC(0-6). Predictive performance was evaluated by assessment of the mean error (ME) and root mean square error (RMSE). Limited sampling strategy (LSS) equations with C2, C4, and C5 provided similar results for prediction of AUC(0-6) (R2 = 0.869, 0.844, and 0.832, respectively). These 3 time points were superior to C0 in the prediction of AUC. The ME was similar for all time points; the RMSE was smallest for C2, C4, and C5. The highest sensitivity index was determined to be 4.9 hours postdose at steady state, suggesting that this time point provides the most information about the AUC(0-12). The results from limited sampling strategies and sensitivity analysis supported the use of a single blood sample at 5 hours postdose as a predictor of both AUC(0-6) and AUC(0-12). A jackknife procedure was used to evaluate the predictive performance of the model, and this demonstrated that collecting a sample at 5 hours after dosing could be considered as the optimal sampling time for predicting AUC(0-6).

Tacrolimus-induced neurotoxicity and nephrotoxicity is ameliorated by administration in the dark phase in rats.

1. Tacrolimus, a potent immunosuppressant, induces impaired renal function and neurological complications. We investigated the influence of dosing time on the neurotoxicity, nephrotoxicity, and immunosuppressive effect of tacrolimus in rats. 2. The repeated injection of tacrolimus in the light phase (8:00) produced a significantly greater increase than that in the dark phase (20:00) in the duration of harmine-induced tremors and in the blood urea nitrogen (BUN) concentration in rats. An immunosuppressive effect of tacrolimus on the xenotransplantation of mouse-to-rat skin grafts was apparent in the dark phase but not in the light phase. 3. The dosing time-dependent pharmacokinetic results were not observed when tacrolimus concentrations in rat whole blood were measured after a single or repeated injection in the light or dark phase. 4. These findings suggest that treatment in the active phase of the diurnal cycle ameliorates neurotoxicity and nephrotoxicity while maintaining the immunosuppressive effect of tacrolimus. The present findings have important implications for therapeutic approaches to avoid tacrolimus-induced neurotoxicity and nephrotoxicity.

Influence of continuous venovenous haemodiafiltration on the pharmacokinetics of tacrolimus in liver transplant recipients with small-for-size grafts.

In adult-to-adult living donor liver transplantation (LDLT), the graft volume is inevitably much smaller than the ideal liver mass (standard liver volume) for the recipient's metabolic demand. Patients with small-for-size grafts are treated with continuous venovenous haemodiafiltration (CVVHD) for the artificial liver support. However, little is known about the influence of CVVHD on the elimination of tacrolimus. The objective of this study was to elucidate the effect of CVVHD on the pharmacokinetics of tacrolimus in recipients of LDLT with small-for-size grafts. Three liver transplant recipients (one male and two females) and donors (two males and one female) were enrolled in this study. Blood samples from inflow port and outflow port were obtained on the first day at the start of CVVHD. Whole-blood concentrations of tacrolimus were measured immediately using the microparticle enzyme immunoassay (MEIA; Abbott Laboratories). There was no significant difference between concentrations of tacrolimus in blood sampled at inflow port and outflow port sites and t(1/2)-values of tacrolimus in the three recipients were 29.9, 63.6 and 28.8 h. CVVHD did not cause a decrease in the blood tacrolimus concentration. Adjustment to the dose or dosing interval is not required for patients treated with tacrolimus during CVVHD.

Evaluation of the new EMIT enzyme immunoassay for the determination of whole-blood tacrolimus concentrations in kidney, heart, and liver transplant recipients

Evaluation of the new EMIT enzyme immunoassay for the determination of whole-blood tacrolimus concentrations in kidney, heart, and liver transplant recipients

Roles of the Jejunum and Ileum in the First-Pass Effect as Absorptive Barriers for Orally Administered Tacrolimus

Background. The immunosuppressant tacrolimus shows poor and variable bioavailability following oral administration in clinical use. Recently, the hepatic and intestinal metabolisms, or first-pass effect, of tacrolimus have been suggested to be responsible for its bioavailability. In the present study, we investigated the respective contribution of the jejunum and ileum to the first-pass effect of tacrolimus in rats.Methods. The metabolism of tacrolimus in everted sacs of the duodenum, jejunum, and ileum was examined. Tacrolimus was administered intravenously or intraintestinally to sham-operated, jejunum-resected, or ileum-resected rats. Blood samples were collected over a 240-min period, and whole-blood tacrolimus concentrations were measured by semiautomated microparticle enzyme immunoassay. The pharmacokinetic parameters of tacrolimus in each group were estimated.Results. The metabolic activity of tacrolimus appeared to be the highest in the everted sacs of the duodenum. The bioavailability of tacrolimus in the jejunum- or ileum-resected rats was higher than that in sham-operated controls. On the other hand, the time to peak concentration in the jejunum-resected rats was about twofold slower than those in ileum-resected and sham-operated rats.Conclusions. These results suggested that the first-pass effect of tacrolimus in the small intestine shows regional differences and the extraction of tacrolimus in the small intestine consists of the amount of extraction in the jejunum and ileum. In addition, the ileum rather than the jejunum as a graft of segmental small bowel transplantation would be useful to avoid the adverse effects of tacrolimus.

Higher intracerebral concentration of tacrolimus after intermittent than continuous administration to rats.

Neurotoxicity associated with tacrolimus after liver transplantation is a serious problem. The optimal way to administer tacrolimus to reduce neurotoxicity remains to be clarified. Three groups of rats were administered tacrolimus for 2 weeks: group C, continuous intravenous infusion (0.25, 0.5, and 1.0 mg/kg/d); group I, intermittent intravenous bolus injection twice daily (0.25, 0.5, and 1.0 mg/kg/d); and group O, oral administration twice daily (5 mg/kg/d; n = 12 each). Rats were killed either day 7 or 14 to measure whole-blood and intracerebral trough concentrations of tacrolimus. The area under the whole-blood concentration-time curve (AUC) was determined day 7. The relative risk ratio of neurotoxicity was evaluated on the basis of the brain to blood concentration ratio (Kp) and intracerebral concentration to AUC ratio (R(AUC)). The whole-blood concentration of tacrolimus and AUC value were greater in group C than group I. Conversely, the intracerebral concentration and Kp and R(AUC) values were significantly greater in group I than group C. The difference in Kp values between groups C and I significantly increased with the dose and duration of administration. Whole-blood and intracerebral concentrations in group O were similar to those at the 0.25-mg/kg/d dose in group I. In conclusion, the intracerebral concentration of tacrolimus was greater after intermittent than continuous administration of the drug. Continuous administration of tacrolimus might be more advantageous than the intermittent method to reduce the intracerebral concentration and neurotoxicity.

Tacrolimus/cerivastatin interaction study in liver transplant recipients

Tacrolimus/cerivastatin interaction study in liver transplant recipients