Beneficial effects of Wuzhi Capsule on tacrolimus blood concentrations in liver transplant patients with different donor-recipient CYP3A5 genotypes.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Its metabolism mainly depends on the cytochrome P450 3A5 (CYP3A5), which has genetic polymorphisms. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A in animal studies in rats. To date, it remains unexplored whether WZC can be efficiently used to enhance the blood concentration of Tac in liver transplant patients with different donor-recipient CYP3A5 genotypes. METHODS: A total of 185 liver transplant patients were enrolled and two-way ANOVA was carried out, then they were divided into four groups according to the combinations of donor-recipient CYP3A5 phenotypes. WZC was given to patients when the dose of Tac was ≥4 mg, and the dose-adjusted C0 (C0 /D) of Tac measured twice in succession was ≤1 ng/ml/mg. The blood trough concentration of Tac (C0 ), C0 /D, and dose- and body weight-adjusted C0 (C0 /D/W) was analysed on days 7 and 14 after liver transplantation. RESULTS: The genotypes of donor and recipient or WZC had significant effects on C0, C0/D and C0/D/W. There were significant differences in the Tac blood concentrations between the groups. The recipient expression (*1)/donor expression (*1) (R+/D+) group had the lowest C0 , C0 /D and C0 /D/W among the four groups. Furthermore, a larger proportion of patients in the CYP3A5 expression groups required Tac dose adjustment to achieve a therapeutic effect and were given Tac with WZC. Notably, the use of WZC significantly increased the blood concentrations of Tac in the CYP3A5 expression groups and greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC in the CYP3A5 expression groups. What is more, WZC reduced the hospitalization cost of patients to a certain extent. WHAT IS NEW AND CONCLUSION: WZC significantly increased the C0 , C0 /D and C0 /D/W in the CYP3A5 expression groups and reduced the hospitalization expenses of patients to a certain extent. What is more, greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC.

Effects and safety evaluation of Wuzhi Capsules combined with tacrolimus for the treatment of kidney transplantation recipients.

WHAT IS KNOWN AND OBJECTIVE: Tacrolimus (FK506), an effective and potent calcineurin inhibitor, is the cornerstone of immunosuppression after kidney transplantation. Wuzhi capsule (WZC), a prescribed ethanol extract of Nan-Wuweizi (Schisandra sphenanthera), is widely prescribed for kidney transplant recipients for the maintenance of tacrolimus concentration in clinical settings. Previous studies have demonstrated that WZC can increase the blood concentration of tacrolimus. However, it remains controversial whether to use WZC can be used to increase tacrolimus concentration in clinical practice. Our study aimed to evaluate the efficacy and safety of WZC combined with tacrolimus in the treatment of kidney transplant recipients. METHODS: One hundred and ninety four Chinese kidney transplant recipients were included in this retrospective study. The recipients were divided into two groups (non-WZC group and WZC group). We investigated the effects of WZC on tacrolimus in terms of tacrolimus metabolism, laboratory tests, pharmacogenomics, renal function and adverse reactions. RESULTS AND DISCUSSION: The concentration/dose (C0 /D) of tacrolimus was significantly higher in the WZC group than the non-WZC group. The laboratory findings of blood routine tests, liver and kidney function were not significantly different between the two groups. The CYP3A5 genotype showed clearly associated with tacrolimus C0 /D, whereas no significant difference was observed in patients with CYP3A4*1B, CYP3A4*22, ABCB1, ABCC2, POR*28 or PXR alleles. The improvement of C0 /D by administration of WZC was significant in CYP3A5 expressers compared to non-expressers. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached the target tacrolimus concentration than the non-WZC group. No significant differences in renal function and adverse reactions were observed between the groups. WHAT IS NEW AND CONCLUSION: Wuzhi capsule can increase tacrolimus concentration without negative effects on renal function and adverse reactions, especially in CYP3A5 expressers. Efficient and economical synergistic effects can be achieved by the combined administration of WZC in kidney transplant recipients.

Marked decrease of tacrolimus blood concentration caused by compound Chinese herbal granules in a patient with refractory nephrotic syndrome.

WHAT IS KNOWN AND OBJECTIVE: The blood concentration of tacrolimus can be affected by co-administrated drugs. The objective is to draw more attention to herb-drug interactions in China, where herbal medicines are commonly used. CASE DESCRIPTION: The blood concentration of tacrolimus in a girl with refractory nephrotic syndrome decreased nearly a half despite no change in dose. Nebulizer therapy, cyclophosphamide and a compound Chinese herbal medicine were the only additional treatments than usual. WHAT IS NEW AND CONCLUSION: The most possible cause of the decrease in tacrolimus concentration was the administration of Radix Astragali among compound Chinese herbal medicine granules.

Co-administration of Wuzhi tablet (Schisandra sphenanthera extract) alters tacrolimus pharmacokinetics in a dose- and time-dependent manner in rats.

ETHNOPHARMACOLOGY RELEVANCE: Tacrolimus is a well-known potent but expensive immunosuppressant. We previously clarified the herb-drug interaction between tacrolimus and Wuzhi tablet (WZ), a prescribed drug of ethanol extract of Schisandra sphenanthera, and showed the ideal effect of WZ on maintaining therapeutic level of tacrolimus and reducing the total drug expense. However, WZ possesses a biphasic effect on regulating CYP3A (the major metabolizing enzyme of tacrolimus), which could induce the mRNA and protein expression after long-term treatment while transiently inhibit the activity of CYP3A. In clinic, clinicians are confused about the relationship between the blood concentration of tacrolimus and the dose and the duration of pretreatment of WZ. Therefore, the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus is urgently needed to be clarified to better combine the use of WZ and tacrolimus in clinic. AIM OF THE STUDY AND METHOD: This study aimed to investigate the effects of the pretreatment time and the dose of WZ on the pharmacokinetics of tacrolimus in rats. RESULTS AND CONCLUSIONS: After pretreated rats with WZ for 0, 0.5, 2, 6, 12 or 24 h, the area under the curve (AUC) of tacrolimus was 2.27 ± 0.59, 1.87 ± 1.14, 2.86 ± 0.64, 1.62 ± 0.70, 1.54 ± 1.06 and 1.12 ± 0.69-fold of that of the tacrolimus alone group, respectively. The ratio of AUC of tacrolimus to that of the co-administration group with 0, 62.5, 125, 250, 500 or 750 mg/kg of WZ was 1.00: 1.07: 1.44: 2.60: 2.32: 2.42, respectively. These findings suggested that WZ increased tacrolimus AUC in a pretreatment time- and dose-dependent manner. In line with the in vivo findings, WZ extract inhibited CYP3A activity in a pre-treatment time- and concentration-dependent manner in human liver microsomes. In conclusion, the pharmacokinetics of tacrolimus was significantly affected by the pretreatment time and the dose of WZ. Oral pretreatment with WZ for 0-2 h or co-dosing of 250 mg/kg of WZ most significantly increased the blood concentration of tacrolimus. These findings would be helpful for guiding the reasonable use of WZ and tacrolimus in clinic.

Effects of Wuzhi Capsules on Blood Concentration of Tacrolimus in Renal Transplant Recipients.

BACKGROUND Tacrolimus is a widely used immunosuppressant in renal transplant recipients. It was demonstrated in rats and healthy volunteers that Wuzhi capsules could inhibit metabolism and maintain blood concentration of tacrolimus. However, there are no clinical studies of Wuzhi capsules in renal transplant recipients. This research aimed to assess the effect of Wuzhi capsules on the blood concentration of tacrolimus in renal transplant recipients. MATERIAL AND METHODS A total of 158 Chinese renal transplant recipients receiving tacrolimus with or without Wuzhi capsules were included in this retrospective study. The cohort study included 126 recipients, with 86 recipients receiving Wuzhi capsules (WZCs) and the other 40 recipients not receiving WZCs. Another 32 recipients were involved in a self-control study. RESULTS Dose- and body weight-adjusted trough concentrations (C0/D/W) of tacrolimus in the WZC group were found to be significantly higher than that in the non-WZC group (P<0.05). The improvement of C0/D/W by administration of Wuzhi capsules was more significant in CYP3A5 expressers than in non-expressers following subgroup analysis. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached target tacrolimus concentration than in the non-WZC group, both in CYP3A5 expressers (P=0.01) and non-expressers (P<0.001). Multiple linear regression analysis and self-control analysis confirmed the positive impact of Wuzhi capsules on tacrolimus concentration (P<0.001). CONCLUSIONS Wuzhi capsules can increase tacrolimus trough concentration without adverse effects on allograft function, especially in CYP3A5 expressers. Efficient and convenient immunosuppressive effects on renal transplant recipients can be achieved by treatment including administration of Wuzhi capsules.

Prediction of Drug-Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically-Based Pharmacokinetic Modelling.

Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug-drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.

Efficacy and Safety of Grapefruit Juice Intake Accompanying Tacrolimus Treatment in Connective Tissue Disease Patients.

Objective It is well known that grapefruit juice (GFJ) elevates the blood tacrolimus (TAC) concentration. We investigated the efficacy and safety of GFJ intake with TAC in cases of connective tissue diseases in which the TAC blood concentration was insufficiently high for clinical improvement, even when 3 mg/day or more of TAC was administered. Methods Seven patients took 200 mL of GFJ every day. The trough levels of the TAC blood concentration were measured before and after GFJ intake and the clinical courses were monitored thereafter. Results First, we surveyed the blood TAC trough levels of 30 recent patients who took 3 mg/day of TAC, and found that 21 patients (70%) did not achieve the minimum target TAC concentration (>5 ng/mL). Seven patients took GFJ due to a lack of efficacy and a relatively low TAC blood concentration. GFJ increased the TAC level from 4.3±2.4 ng/mL to 13.8±6.9 ng/mL (average increase: 3.3-fold). GFJ was also effective in achieving a clinical improvement in most cases without causing any severe adverse events, and it helped to decrease the dosages of glucocorticoid and TAC. In some cases, the blood TAC concentration fluctuated for no apparent reason. Conclusion GFJ intake was effective for the elevation of TAC concentration by approximately three fold and clinical improvement, but special care is required for monitoring its influence on concomitantly used drugs as well as TAC concentration. The addition of GFJ to TAC treatment could be an efficacious treatment option, when the plasma TAC concentration does not reach the minimal target concentration.

Effects of Wuzhi capsule on blood concentration of tacrolimus after renal transplantation.

This study aimed to investigate the effects of Wuzhi capsule on blood concentration of tacrolimus after renal transplantation. Sixty patients after allogenic renal transplantation were enrolled in this study and randomly divided into an experimental group and a control group. One oral Wuzhi capsule was taken in the morning and evening for patients in the experimental group, while none was given to the control group, maintaining the trough blood concentration of tacrolimus in the normal range. After 3 weeks, the changes of tacrolimus dosage and hepatorenal function in the two groups were compared. Comparisons of drug dosage and blood concentration C0 value of tacrolimus before initiating the experiment showed that there was no statistically ignificant difference (P>0.05) between the two groups. The differences of blood concentration of tacrolimus and hepatorenal function for patients in both two groups after 3 weeks’ treatment also showed no statistical significance (P>0.05), whereas a statistically significant decrease was demonstrated in the tacrolimus dosage of the Wuzhi capsule group compared with that of the control group (P=0.0083). After renal transplantation, Wuzhi capsules were added so as to enable tacrolimus to reach a suitable blood concentration, which can prevent the occurrence of renal transplantation rejection, thus alleviating the economic burden of patients and producing larger social benefits.

Clinically Significant Drug Interaction Between Clotrimazole and Tacrolimus in Pancreas Transplant Recipients and Associated Risk of Allograft Rejection.

STUDY OBJECTIVE: To examine the clinical significance of clotrimazole troche discontinuation on tacrolimus trough levels and risk of allograft rejection after pancreas transplantation. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: Sixty-five pancreas transplant recipients (simultaneous pancreas-kidney transplants [39 patients], pancreas after kidney transplants [4 patients], and pancreas transplant alone [22 patients]) who were discharged after transplantation receiving a maintenance immunosuppressive regimen of tacrolimus, mycophenolate, and prednisone, and a clotrimazole troche to prevent oral mucosal candidiasis; per protocol, the clotrimazole troche was discontinued at 3 months after transplantation. MEASUREMENTS AND MAIN RESULTS: Patients were followed for 1 year after transplantation. The primary outcome measure was the difference in tacrolimus trough level before and after discontinuation of the clotrimazole troche. The secondary outcome measure was the difference in tacrolimus trough level when patients were stratified by the cohort that had a documented rejection episode 3-12 months after transplantation (rejection group) and the cohort that did not experience a rejection episode (no-rejection group). The incidence of rejection was evaluated in relation to mean tacrolimus trough concentrations above or below a protocol-defined level of significance (6 ng/ml). For the primary outcome, the mean tacrolimus trough level before discontinuation of the clotrimazole troche was significantly higher than the mean trough level after discontinuation (mean ± SD 9.6 ± 3.0 ng/ml vs 7.1 ± 2.6 ng/ml, p = 0.000003). For the secondary outcome, the mean tacrolimus trough level difference before and after clotrimazole troche discontinuation remained significant in both the no-rejection group (9.5 ± 3.0 ng/ml vs 7.4 ± 2.4 ng/ml, p = 0.00007) and rejection group (10.9 ± 3.3 ng/ml vs 4.1 ± 2.5 ng/ml, p = 0.0008). Between groups, the mean tacrolimus serum trough level after clotrimazole troche discontinuation was lower in the rejection group (4.1 ± 2.5 ng/ml) than that in the no-rejection group (7.4 ± 2.4 ng/ml; p = 0.005). The mean tacrolimus trough level difference between before and after discontinuation was greater in the rejection group (6.8 ± 1.5 ng/ml) versus the no-rejection group (2.1 ± 3.8 ng/ml, p = 0.009). Tacrolimus trough levels below 6 ng/ml (19 patients) after clotrimazole troche discontinuation were associated with an increased incidence of rejection episodes within 3-12 months after transplantation (odds ratio 12, 95% confidence interval 1.24-115.91, p = 0.032) versus trough levels of 6 ng/ml or higher (46 patients). CONCLUSION: Clotrimazole troche discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions. In addition, when trough levels are below 6 ng/ml, these fluctuations may contribute to the occurrence of allograft rejection.

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury.

Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.

Multifaceted interaction of the traditional Chinese medicinal herb Schisandra chinensis with cytochrome P450-mediated drug metabolism in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (SC), officially listed as a sedative and tonic in the Chinese Pharmacopoeia, has been used as a common component in various prescriptions in Traditional Chinese Medicine (TCM) and more recently in western medicine for its antihepatotoxic effect. To assess the possible herb-drug interaction, effects of SC extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied. MATERIAL AND METHODS: Effects of SC extracts on rat hepatic CYP450 enzymes in vitro and in vivo were investigated by probe substrates method, real-time RT-PCR assay and Western blotting analysis. Furthermore, the effects of SC alcoholic extract on the PK of four SC lignans and the drugs possibly co-administrated in vivo were studied in male Sprague-Dawley rat. RESULTS: SC aqueous extract and alcoholic extract showed significant inhibitory effect on the activities of rat liver microsomal CYP1A2, 2C6, 2C11, 2D2, 2E1 and 3A1/2 in vitro. Multiple administrations of SC aqueous extract (1.5g/kg, qd×7d) and alcoholic extract (1.5g/kg, qd×7d) increased the activities, mRNA and protein expressions of CYP2E1 and CYP3A1/2, and meanwhile, inhibited the activities and mRNA expression of CYP2D2 in vivo. The in vivo metabolism of four SC lignans, such as schisandrin, schisantherin A, deoxyshisandrin and γ-schisandrin, and chlorzoxazone was significantly accelerated, exhibited by the reduced AUC and increased CLz/F, by 7-day pretreatment with SC alcoholic extract. However, both single and multiple dosing treatments of SC alcoholic extract remarkably decreased the in vivo metabolism of tacrolimus indicated by the enhanced AUC (7-12 fold) and elevated Cmax (10 fold). CONCLUSION: These results revealed that the SC extracts exhibited multifaceted effects on rat hepatic CYP450 enzymes. Herb-drug interaction should be paid intense attention between SC components and drugs metabolized by different CYP450 enzymes.

The effect of magnesium supplements on early post-transplantation glucose metabolism: a randomized controlled trial.

Post-transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post-transplantation. We conducted a single-center, open-label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). Analyses were on intention-to-treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI -1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA-IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

Topical tacrolimus therapy for antibiotic-refractory pouchitis.

BACKGROUND: Pouchitis is the most common complication after restorative proctocolectomy for ulcerative colitis, and it leads to pouch failure. The administration of oral antibiotics is the main treatment for pouchitis; however, in some cases, antibiotic-refractory pouchitis may develop, which requires further medical therapy. OBJECTIVE: We investigated the applicability of topical tacrolimus for refractory pouchitis. DESIGN: We performed a prospective pilot study. The study protocols were registered with the University Hospital Medical Information Network Clinical Trials Registry, 000006658. SETTING: This study was conducted in the Surgical Department of Hyogo College of Medicine. PATIENTS: Patients with antibiotic-refractory pouchitis were treated for 8 weeks with a tacrolimus enema. MAIN OUTCOME MEASURES: The efficacy was assessed by comparing Pouchitis Disease Activity Index scores. Safety was assessed by measuring whole blood tacrolimus trough levels. RESULTS: Ten patients with refractory pouchitis were enrolled. No severe adverse events occurred. The mean scores decreased from 15.9 ± 0.8 to 7.8 ± 0.8 during 8 weeks of treatment (p < 0.01). Specifically, the clinical symptom, endoscopic finding, and histological finding subscores decreased to 0.8 ± 0.6, 3.9 ± 0.2, and 2.9 ± 0.4. Nine patients recovered from their clinical symptoms, and 3 patients recovered from pouchitis. LIMITATIONS: This small study was neither blinded nor randomized. CONCLUSIONS: This study demonstrates that the use of topical tacrolimus for the treatment of refractory pouchitis is safe and effective in the short term for clinical symptoms. Although complete endoscopic healing was not achieved, this treatment may have early rescue efficacy in the treatment of antibiotic-refractory pouchitis.

Steroid withdrawal based on lymphocyte sensitivity to endogenous steroid in renal transplant recipients.

Though steroid withdrawal is done in many renal transplant recipients, some patients must restart steroids. Little report has investigated steroid withdrawal under pharmacodynamic monitoring. We assessed lymphocyte sensitivity to endogenous cortisol as a biomarker for determining the safety of steroid withdrawal in renal transplant patients, as we hypothesized that patients hyposensitive to cortisol could not be sufficiently immunosuppressed by their intrinsic cortisol as a substitute for the reduced or withdrawn steroid. Lymphocyte sensitivity to cortisol was examined in 30 long stable renal transplant recipients. Lymphocyte sensitivity to cortisol and its relationship with the clinical outcome after steroid reduction and withdrawal was investigated. The lymphocyte sensitivities to cortisol were estimated as IC(50) of lymphocyte blastogenesis. The lymphocyte proliferation rate for concentration of serum cortisol compared between incident and non-incident groups. Serum creatinine levels (S-Cr) increased in a significantly higher number of patients hyposensitive to cortisol (IC(50)≧10000 ng/ml) than in normally sensitive patients (IC(50)<10000 ng/ml). The incidences of steroid withdrawal syndrome and necessity for increasing steroid dose or restarting steroid administration were also higher in the patients hyposensitive to cortisol. The patients in whom the lymphocyte proliferation rate was less than 60% did not show increase in S-Cr, experience steroid withdrawal symptoms, or require an increase in the steroid dose or restart of steroid administration. The patients who have the normal IC(50) values of cortisol, can withdraw steroid more safely. The lymphocyte sensitivity to cortisol may be a useful biomarker for selecting patients who can sustain steroid withdrawal.

[Study on the clinical application of wuzhi capsule after renal transplantation].

OBJECTIVE: To study the protection of Gan by using deoxyschizandrin (Wuzhi Capsule, WC) in the renal transplantation recipients while increasing the blood concentration of tacrolimus (Tac). METHODS: Seventy-three renal transplant recipients were randomly assigned to two groups, i.e., 35 in the WC group and 38 in the control group. All patients received Tac + MMF + Pred triple immunosuppressive therapy. WC was additionally given to patients in the WC group. One year was taken as one therapeutic course. Changes of the blood concentration of Tac were detected one week, 1, 3, 6, and 12 months after medication in the two groups using microparticle enzyme immune assay (MEIA). Meanwhile, the liver and kidney functions, and the blood glucose were tested. RESULTS: One week after the application of WC, the blood Tac concentration increased 67.2% averagely. During the 1 -12 months of WC treatment, the Tac dosage was significantly lower in the WC group than in the control group (P<0.01). There was no significant difference in the liver and renal functions, or the blood glucose levels between the two groups (P>0.05). CONCLUSION: WC could significantly increase the blood Tac concentration of renal transplant recipients, reduce their Tac dosages, with no obvious adverse reaction.

Citrus grandis peel increases the bioavailability of cyclosporine and tacrolimus, two important immunosuppressants, in rats.

Citrus grandis peel (CGP) is a beverage ingredient and a medicinal herb in Oriental countries. Cyclosporine and tacrolimus, important immunosuppressants with narrow therapeutic windows, are widely used in transplant patients. This study investigated the effects of co-administering CGP on the bioavailability of cyclosporine and tacrolimus. Male Sprague-Dawley rats were orally administered tacrolimus or cyclosporine with and without CGP. The concentrations of cyclosporine and tacrolimus in blood were assayed by monoclonal fluorescence polarization immunoassay and microparticle enzyme immunoassay, respectively. P-glycoprotein- and cytochrome P 450 3A4 (CYP3A4)-associated mechanisms were investigated by using everted rat intestinal sac and recombinant CYP3A4 isozyme. The results showed that CGP significantly increased the bioavailability of cyclosporine and tacrolimus by 100.0% and 234.7%, respectively. Ex vivo studies indicated that the interaction was mediated by the inhibition of CYP3A4. We suggest that CGP is contraindicated for transplant patients treated with cyclosporine or tacrolimus to minimize the risk of intoxication.

Local immune regulation of mucosal inflammation by tacrolimus.

PURPOSE: Tacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgroup of proctitis patients. This study aimed to evaluate whether colonic mucosal immune cells are susceptible to locally applied tacrolimus in vitro. Our in vivo studies aimed at evaluating whether local tacrolimus treatment in mice would bring about local immune suppression and to compare colonic and systemic tacrolimus levels after locally and systemically applied tacrolimus. RESULTS: In vitro tacrolimus inhibited the activation of multiple cell types present in colonic tissue; lamina propria T cells, NKT cells, and both classical- and non- classical antigen presenting cells. However, the cytokine production of epithelial cells was not inhibited by tacrolimus at these concentrations. After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice. Moreover, rectally applied tacrolimus resulted in a local but not a systemic immune suppression in mice. CONCLUSIONS: Tacrolimus inhibits activation of several pivotal immune cells of the intestinal mucosa. Murine studies indicate that colonic application of tacrolimus induces local rather than systemic immune suppression.