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Acute overdose of tacrolimus appears to cause no or minimal adverse clinical consequences. We encountered a pediatric case who underwent liver transplantation associated with hepatic artery thrombosis (HAT), which recurred following acute tacrolimus overdose. A 10-month-old girl underwent living-related liver transplantation because of biliary atresia. To reconstruct the hepatic artery, the right gastroepiploic artery of the donor was interposed between the right hepatic artery of the recipient (2.5 mm in diameter) and the left hepatic graft artery (1 mm in diameter) under microscopy. On postoperative day 4, Doppler ultrasonography showed a remarkable reduction in hepatic arterial flow, which was consistent with HAT. The patient underwent immediate hepatic arteriography and balloon angioplasty. The stenotic sites were dilated by the procedure. Tacrolimus was infused intravenously after transplantation and the infusion rate was adjusted to achieve a target concentration of 18-22 ng/mL, which remained stable until the morning of day 6. An unexpectedly high blood concentration of tacrolimus (57.4 ng/mL) was detected at 6:00 PM on day 6, and tacrolimus was discontinued at 9:00 PM; however, the tacrolimus level reached 119.5 ng/mL at 0:00 h on day 7. While the concentration decreased to 55.2 ng/mL on the morning of day 7, the hepatic arterial flow could not be observed by Doppler ultrasonography. Emergent hepatic arteriography showed stenosis of the artery at the proximal site of the anastomosis. Balloon angioplasty was again performed and the stenotic site was successfully dilated. High level of tacrolimus exposure to the hepatic artery with injured endothelium by preceding angioplasty may have been related to the recurrence of HAT in the present case.

We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.

Reductions in hepatic oxygen supply may reduce the oxidative metabolism of drugs, including tacrolimus. We encountered a patient (2.3-year-old girl) with hypoxemia [arterial oxygen tension (PaO2) 40.9 mmHg in room air] due to hepatopulmonary syndrome who had undergone living related liver transplantation. After transplantation, tacrolimus was initially administered by continuous intravenous infusion, and her PaO2 was maintained at more than 50 mmHg [72.8+/-10.4 (SD) mmHg] by oxygen supplementation. Apparent clearance of tacrolimus (calculated as: the infusion rate of tacrolimus/blood concentration) in the patient (0.075 l/h per kg) was comparable to those of non-hypoxemic control pediatric cases (0.092+/-0.014 l/h per kg, n=7, mean age 2.2 years, PaO2 149.2+/-41.5 mmHg), except for the acute decline in the early period after transplantation. These findings suggest that the reduction in tacrolimus clearance is negligible when arterial oxygen tension is maintained at more than 50 mmHg, even in patients with hypoxemia.

The objective of this study was to characterize the pharmacokinetics and immunosuppression of a tacrolimus-loaded biodegradable microsphere (TLBM) in rats. We prepared TLBM. DA/Slc rats were given TLBM at a dose of 1.6 mg/kg (n = 9), 2.4 mg/kg (n = 5), or 7.2 mg/kg (n = 7) tacrolimus contents by a single subcutaneous administration to achieve sustained release over a long period. DA/Slc rats were given TLBM by a single subcutaneous administration at a dose of 4.8 mg/kg (n = 6) tacrolimus contents to clarify the main site of TLBM uptake in the organs. In the rat liver transplantation model, the recipients were given TLBM at a dose of 0.16 mg/kg (n = 5), 2.4 mg/kg (n = 4), or 4.8 mg/kg (n = 5) tacrolimus contents by a single subcutaneous administration on the first day after operation. Overall survival days were compared. Continuous flat parallel concentration profiles were significant for 10 days from the first day after a single subcutaneous administration of TLBM (P <.01). The relationship between the dosages of TLBM administration and area under the concentration-time curve (AUC) up to 18 days demonstrated a linear regression line (P <.01). In addition, the relationship between the dose of TLBM and the survival days of the recipients in the liver transplantation model showed a positive correlation. The current pharmacokinetic study of TLBM revealed significantly increased tacrolimus levels in the regional lymph nodes compared with other organs except bone marrow (P <.01). In conclusion, TLBM allowed tacrolimus to release gradually in a very stable manner for 10 days, with dose-dependent immunosuppression after a single subcutaneous administration. The main site of TLBM uptake after subcutaneous administration was the regional lymph node of administration site.

The optimal doses of tacrolimus (FK) needed to reach and maintain a target blood level vary among cases of living donor liver transplantation (LDLT). One hundred and twenty four LDLTs in 122 patients were included in this study. Tacrolimus was administered by continuous intravenous infusion at a rate of 2.5 microg/kg/h just after the operation. The time needed to reach the target blood level and the dose needed to maintain this level for 1 week (17-18 ng/mL) were defined as the initial duration (ID) and secondary dose (SD), respectively. In the first 100 LDLTs, the correlations between ID or SD and some clinical factors were examined and equations for predicting ID or SD were derived. In the latest 24 LDLTs, FK was administered using these equations and the actual and calculated ID and SD values were compared. A multiple regression analysis revealed that only the graft weight/recipient standard liver volume (GW/SLV) ratio (%) correlated with ID or SD. Stepwise regression analysis led to the equations ID (h) = 0.4 x GW/SLV ratio + 0.2; SD (microg/kg/h) = 0.02 x GW/SLV ratio - 0.4. Simple regression analysis revealed a significant correlation between the actual and calculated ID and SD values (p < 0.0001). Initial duration and SD can be estimated from equations using the GW/SLV ratio.

Background: If long-term organ cryopreservation can be attained, a significant achievement will have been made to address the problem for donor shortage. Fetal intestine has been known to revascularize naturally without vascular anastmosis. The authors have confirmed previously that the newborn intestine also could develop to maturity in the host omentum. Here, the authors examined whether the cryopreserved newborn intestine could revascularize in the syngeneic combination using the 2 different solutions and whether cryopreservation affect their antigenicity in the allogeneic combination., Methods: Inbred rat strains of LEW (MHC haplotype; RT1(l)) and BN (RT1(n)) were used. LEW newborn intestinal grafts were stored in RPMI-1640 or University of Wisconsin solution with 10% DEMSO (n = 10 in each group). The grafts were placed into a cold (4 degrees C) preservation solution for 30 minutes and then placed into a freezing chamber and cooled to -80 degrees C at -1 degrees C/min after 12 hours quenched to -180 degrees C in liquid nitrogen for longer than 30 days. Then, the cryopreserved grafts under the 2 different solutions were transplanted syngenicaly (LEW to LEW). The cryopreserved BN grafts also were implanted into the LEW omentum pouch. The allotransplantation was received with a 14-day high-dose course of tacrolimus (0.64 mg/kg, intramuscularly). The grafts were evaluated histologically at 4 weeks after transplantation. Fresh newborn intestines implanted in this syngeneic and allogeneic combination were evaluated as each control group., Result: In the syngeneic combination, more than 90% of the mature intestine were obtained. There was no significant difference among the different solution and the fresh group. However, in the allogeneic combination, both fresh and cryopreserved grafts were histologically poor., Conclusions: This is the first report showing that long-term cryopreservation was not harmful for neovascularization of newborn intestine. Long-term cryopreservation did not reduce the antigenicity of the newborn intestine. J Pediatr Surg 36:602-604., (Copyright 2001 by W.B. Saunders Company.)

Cholestatic effects have been reported for cyclosporine (CsA), but information is still limited for tacrolimus (TCR). The purpose of this study was to investigate the influence of TCR on biliary bile acid and lipid composition as compared with CsA, using a continuously bile-drained rat model. Adult male Wistar rats received TCR (0.4 mg/kg, 1 mg/kg, and 4 mg/kg) or CsA (2.5 mg/kg, 10 mg/kg, and 25 mg/kg) by intramuscular injection (i.m.) daily for 10 days. On day 7, the common bile duct of all rats was cannulated, then bile was continuously collected for the following 3 days. Bile flow, bile acid secretion rate (BASR), and biliary lipids secretion were measured for each of the groups. TCR increased bile acid-dependent flow (BADF) but with no statistical significance. However, this agent did not influence total bile flow and biliary lipids secretion, while bile acid-independent flow (BAIF) was significantly reduced and bile acid synthesis (mainly cholic acid, CA, synthesis) was increased. In contrast, CsA was cholestatic, showing a tendency to reduce both BADF and BAIF. BASR was dose-dependently suppressed, especially in chenodeoxycholic acid (CDCA). Furthermore, biliary lipids secretions were also significantly decreased under a higher dose of CsA. TCR increased BADF with no influence on total bile flow, having a stimulating effect on CA production, although CsA dose-dependently diminishes CDCA production and consequently reduced bile secretion. Our results suggest that TCR is a less effective agent on cholestasis as compared to CsA.