A model based on readily defined behaviours and psychosocial factors predicted relapse to harmful drinking after transplant for ALD. This model may improve assessment and post-transplant management of patients with advanced ALD.

AimsTherapeutic drug monitoring (TDM) of tacrolimus is complicated by conflicting data on the correlation between tacrolimus trough blood concentrations and the incidence of rejection. The aim of this cross-sectional study was to investigate the blood distribution and protein binding of tacrolimus in liver transplant recipients to explore better predictors of clinical outcome. MethodsBlood and plasma distribution of 3 H-dihydro-tacrolimus was investigated in 40 liver transplant recipients using Ficoll Paque and density gradient ultracentrifugation, respectively, and equilibrium dialysis to investigate plasma protein binding. ResultsIn blood tacrolimus was mainly associated with the erythrocyte fraction (83.2%, range 74.6-94.9%), followed by diluted plasma (16.1%, range 4.5-24.9%), and lymphocyte fraction (0.61%, range: 0.11-1.53%). In plasma, lipoprotein deficient serum fraction (54.2%, range 38.5-68.2%) was the main reservoir of tacrolimus. The unbound fraction of tacrolimus was found to be 0.47 ± 0.18% (range 0.07-0.89%). The percentage of tacrolimus associated with the lymphocy tes (0.8 ± 0.4 vs 0.3 ± 0.1%, P = 0.012) and estimated unbound concentration (0.42 ± 0.21 ng l -1 vs 0.24 ± 0.08 ng l -1 , P < 0.001) of tacrolimus were significantly different in stable transplant recipients and those experiencing rejection. Haematocrit and red blood cell count significantly influenced the percentage of tacrolimus associated with erythrocytes. The fraction unbound of tacrolimus was correlated with a 1 -acid glycoprotein and high density lipoprotein cholesterol concentrations. ConclusionsTacrolimus unbound concentration was observed to be lower in liver transplant recipients experiencing rejection and further study is required to evaluate its utility in the TDM of tacrolimus.

The goal was to study the factors affecting tacrolimus apparent clearance (CL/F) in adult liver transplant recipients. Tacrolimus dose and concentration data (n = 694) were obtained from 67 liver transplant recipients (22 female and 45 male), and the data were analyzed using a nonlinear mixed-effect modeling (NONMEM) method. A 1-compartment pharmacokinetic model with first-order elimination, an absorption rate constant fixed at 4.5 hours, and first-order conditional estimation was used to describe tacrolimus disposition. The predictive performance of the final model was evaluated using data splitting and assessing bias and precision of the estimates. The population estimate of tacrolimus CL/F and apparent volume of distribution (V/F) were found to be 21.3 L/h (95% confidence interval, CI, 18.0-24.6 L/h) and 316.1 L (95% CI 133-495 L), respectively. Neither patient's age, weight, gender, nor markers of liver function influenced tacrolimus CL/F. The final model was TVCL = 21.3 + 9.8 x (1 - HEM) + 3.4 x (1 - ALB) - 2.1 x (1 - DIL) - 7.4 x (1 - FLU), where TVCL, typical estimate of apparent clearance, HEM = 0 if hematocrit <35%, otherwise 1; ALB = 0 if albumin <3.5 g/dL, otherwise 1; DIL = 0 if diltiazem is coadministered, otherwise 1; FLU = 0 if fluconazole is coadministered, otherwise 1. This study identified the factors that significantly affect tacrolimus disposition in adult liver transplant recipients during the early posttransplantation period. This information will be helpful to clinicians for dose individualization of tacrolimus in liver transplant recipients with different clinical conditions including anemia or hypoalbuminemia or in those patients receiving diltiazem or fluconazole.

Therapeutic drug monitoring of tacrolimus is complicated by the conflicting evidence of a relationship between trough blood tacrolimus concentration and clinical outcome. This prospective study investigated the blood distribution and protein binding of tacrolimus in liver transplant recipients over the first 60 days after transplantation with a view to identifying possible predictors of clinical outcome. Blood samples were collected from 10 liver transplant recipients on days 1, 7, and 60 after the initiation of tacrolimus therapy, and the distribution of tacrolimus in blood and the plasma protein binding were investigated. The unbound concentration of tacrolimus in plasma was estimated. Graft status was assessed using liver function tests and liver biopsies. The association of tacrolimus with erythrocytes varied significantly (74.4 +/- 5.0% vs 80.4 +/- 3.4%; P = 0.034) from day 1 to day 60. In plasma, tacrolimus mainly associated with lipoprotein-deficient plasma (60.1 +/- 6.5%), followed by high-density lipoproteins (27.2 +/- 6.6%), low-density lipoproteins (10.0 +/- 4.2%), and very low-density lipoproteins (2.8 +/- 1.8%). The percentage of tacrolimus associated with leukocytes (1.10 +/- 0.40% vs 0.40 +/- 0.09%; P = 0.0003) and the unbound concentration of tacrolimus (0.70 +/- 0.19 vs 0.28 +/- 0.04 ng/L; P < 0.0001) were observed to be significantly lower during episodes of rejection. In patients experiencing tacrolimus-related side effects, only the unbound concentration of tacrolimus was found to be significantly higher (0.84 +/- 0.19 vs 0.53 +/- 0.19 ng/L; P < 0.0001), and blood concentrations were not different (9.2 +/- 2.2 vs 8.1 +/- 1.8 ng/mL; P = 0.1). Blood distribution and protein binding of tacrolimus vary significantly over the posttransplantation period, leading to changes in its unbound concentration. A prospective study in a larger cohort of patients is required to establish the role of blood distribution and protein binding of tacrolimus in its therapeutic drug monitoring.

SUMMARYBackground: There have been a number of reports of colitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs) and salicylates. Aim: To conduct a case-control analysis of new cases of colitis, with particular reference to the usage of NSAIDs and salicylates prior to the development of the disease. Methods: One hundred and five consecutive new cases of colitis presenting to a single gastroenterologist were questioned about their recent usage of NSAIDs and salicylates. For comparison, the frequency of usage of these compounds was studied in two groups of 105 ageand sex-matched controls taken from hospital in-patients and community cases attending the Accident and Emergency Department.

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SUMMARY Two patients with primary biliary cirrhosis who were increasingly incapacitated by xanthomatous neuropathy are described. Treatment with a low fat diet and cholestyramine was unhelpful but repeated plasmaphoresis by simple venesection in one and plasma exchange using an IBM blood cell separator in the other over a period of several months completely relieved the symptoms of the neuropathy, caused skin xanthomata to recede, and lowered plasma lipid levels in both patients. There was no evidence that this procedure was associated with any deleterious effects on the liver. The size of the cholesterol pool in xanthomata in one patient was estimated to be approximately 35 g, and from the plasma cholesterol response to plasmaphoresis at varying frequency it was suggested that the excess of cholesterol synthesis over degradation was less than 0.3 g/day in one patient and less than 0.4 g/day in the other. On the basis of the response in these patients it is suggested that the turnover rates of lipid pools are relatively slow in biliary cirrhosis and that cholesterol accumulation is more likely to be due to a reduced catabolic rate than to an increased synthetic rate of cholesterol. Plasmaphoresis or plasma exchange are useful methods of treatment for the rare patient afflicted by this resistant and distressing complication of biliary cirrhosis.

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