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Background: Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect., Methods: Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis., Results: Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45 cells, and reduced numbers of F4/80 macrophages, and CD3 T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice., Conclusions: Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.

Background: The data on lipid profile in renal transplant recipients from the Indian subcontinent is scant., Methods: Lipid profile was studied in 30 consecutive patients of end stage renal disease before renal transplantation (0 month) and prospectively posttransplantation at 1, 3, and 6 months. The results were compared with 30, age and sex matched, healthy controls. All the patients received triple immunosuppression (prednisolone, azathioprine and cyclosporine)., Results: Pretransplantation, the hypertriglyceridemia and hypercholesterolemia was present in 20% and 7% of the patients and the difference (elevation) in the mean values of various lipid fractions was not significant compared to healthy controls except a fall in HDL (p < .01). After renal transplantation, there was a significant elevation in the mean values of total cholesterol, triglycerides, VLDL, and LDL cholesterol at 1, 3, and 6 months. HDL cholesterol levels remained significantly lower as compared to healthy controls. Although, the mean values of serum triglycerides and cholesterol were significantly higher in diabetic end stage renal disease compared to nondiabetic ESRD, however there was insignificant difference in the lipid profile amongst diabetic and nondiabetic renal allograft recipients., Conclusion: Our data shows distinct elevation in the lipids and lipoproteins after renal transplantation and immunosuppressive drugs seem to be the culprit.

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.

Kidney transplant patients receiving phenytoin or phenobarbital may have decreased graft survival. These drugs have been shown to enhance the metabolism of glucocorticoids. We determined the disposition of total and unbound prednisolone in six stable kidney transplant patients receiving prednisone for immunosuppression and phenytoin or phenobarbital for a seizure disorder. Six similar patients not on anticonvulsants served as controls. A single intravenous dose of prednisolone was administered, and plasma samples were analyzed for prednisolone using a high-performance liquid chromatographic assay. Equilibrium dialysis was used to determine unbound prednisolone concentrations. Pharmacokinetic analysis showed that the half-life of prednisolone was shorter in the anticonvulsant group compared to the controls, based on both total (2.3 +/- 0.4 vs. 3.4 +/- 0.2 hr (SD), P less than 0.01) and unbound (1.7 +/- 0.3 vs. 2.4 +/- 0.2 hr, P less than 0.01) concentrations. Total drug clearance was 10.4 +/- 2.8 liters/hr (0.171 +/- 0.087 liters/hr X kg) in the anticonvulsant group versus 7.2 +/- 1.2 liters/hr (0.100 +/- 0.014 liters/hr X kg) in the controls (P less than 0.05). Unbound prednisolone clearance was 57.2 +/- 12.1 versus 46.4 +/- 8.7 liters/hr (P greater than 0.05) and for weight-corrected estimates 0.886 +/- 0.224 liters/hr X kg versus 0.644 +/- 0.115 liters/hr X kg (P less than 0.05) in the two groups, respectively. Thus, the disposition of prednisolone is altered by anticonvulsants in kidney transplant patients and may require dose alteration.

Although prednisolone is the most common immunosuppressive agent used in renal transplantation, an accurate formulation of the optimal dose regimen remains to be established. A sensitive and precise radioimmunoassay was developed for this purpose. Fifty microliters of 1:20 dilutions of serum or 1:200 dilutions of urine were incubated at room temperature for two hours with 130 pg of 3H-prednisolone (150muCi/microgram) and a rabbit antiserum against prednisolone (1:1,600 dilution). Serial prednisolone clearances (Cp) for ten renal transplant patients representing variable allograft functions were compared with their corresponding creatine clearances (Cer). The data show that renal metabolism of prednisolone is well correlated with Ccr. Increasing (decreasing) Ccr is accompanied by increasing (decreasing) Cp. The availability of an assay for serum prednisolone, together with a knowledge of the ratio between these two clearances, may prove useful for regulating therapy in renal transplant patients.

The following investigation was performed to establish whether renal transplant patients treated with cyclosporine and prednisone have a decreased prednisolone catabolism and/or an increased systemic availability of oral prednisone when compared with patients treated with azathioprine and prednisone. Therefore we assessed, by HPLC and equilibrium dialysis, the total concentrations of prednisolone and prednisone and the unbound concentrations of prednisolone in plasma samples collected over 24 hr, and the 24-hr urinary excretion of prednisolone, prednisone, and 6 beta-hydroxyprednisolone after an i.v. dose of prednisolone and an equal oral dose of prednisone in 25 renal transplant patients on cyclosporine and in 25 patients on azathioprine and prednisone one month after transplantation. The metabolic clearance, the renal clearance, the volume of distribution, and the systemic availability of total and unbound prednisolone were identical in patients with and without cyclosporine. The apparent activities of the oxidoreductases involved in the biotransformation of prednisone into prednisolone and vice-versa were not affected by cyclosporine therapy. The fractional urinary excretions of 6 beta-hydroxyprednisolone increased with increasing metabolic clearance rate of prednisolone (r = 0.50, P less than 0.001). This relationship was not modulated by cyclosporine, indicating that cyclosporine does not affect the activity of the microsomal P-450-dependent 6 beta-hydroxylase. Thus, early after transplantation, patients on cyclosporine have a normal metabolism of prednisolone.

Prednisone and prednisolone are drugs with the potential for therapeutic inequivalence due to bioavailability problems. The objective of our study was to compare the systemic bioavailability of prednisolone from oral prednisone and prednisolone. Nine kidney transplant patients receiving prednisone (12.5 to 22.5 mg per day) were administered, in a randomized fashion, the same dose of oral prednisone (Deltasone), oral prednisolone (Delta-cortef) and intravenous prednisolone (Hydeltrasol). Prednisolone and prednisone levels were measured using a specific high-pressure liquid chromatographic assay. Since prednisolone exhibits dose-dependent pharmacokinetics because of nonlinear plasma protein binding, bioavailability from oral prednisone and oral prednisolone, compared to the intravenous dose, was 84.5 +/- 17.8% and 95.5 +/- 17.6% using unbound drug concentrations. These differences were not statistically significant. Furthermore, no significant differences were observed between the two oral formulations in peak prednisolone levels, time of peak levels or half-life using either total or unbound drug concentrations. The results from our study indicate that both of the oral preparations tested provide similar bioavailability of active prednisolone and the conversion of prednisone to prednisolone occurs rapidly.

Prednisolone pharmacokinetics and protein binding have been compared in 16 cushingoid and 46 non-cushingoid long-term kidney transplant recipients. After oral administration of 10 mg prednisolone, the cushingoid patients had a significantly higher peak prednisolone serum concentration (P less than 0.03), a longer elimination half-time (P less than 0.03), and a larger area under the time-concentration curve of total (P less than 0.01) and free (P less than 0.03) prednisolone. The apparent total body clearance of total and free prednisolone was significantly lower in the cushingoid than in the non-cushingoid patients (P less than 0.02 and less than 0.05, respectively). There was no significant difference in time of peak concentration, apparent volume of distribution or serum protein binding of prednisolone. It is suggested that the development and persistency of some cushingoid features may be related to a decreased total body clearance of prednisolone, which, in turn, may be influenced by impaired renal function.

In the first randomised study of cyclosporine in Denmark 43 cadaveric kidney recipients were treated either with cyclosporine (Cys) and prednisone or azathioprine (Aza) and prednisone. The degradation of prednisolone was examined in 18 of these patients. The 12 month graft survival of the Cys group was not significantly greater than that of the Aza group (68% and 60%, respectively), but fewer rejection episodes occurred in the Cys group (p less than 0.05). The degradation of prednisolone was significantly decreased in the Cys group compared to the Aza group. Accordingly, plasma half-lives of prednisolone were increased in the Cys group compared with the Aza group. As a decreased degradation of prednisolone during Cys treatment may lead to increased steroid activity, we recommend that a reduction of the prednisone dosage during Cys treatment is safe.

Kidney transplant patients receive chronic prednisone and azathioprine for immunosuppression. However, the effect of azathioprine on prednisolone pharmacokinetics has not been determined in this population. Total and unbound prednisolone concentrations were determined, using high performance liquid chromatography and equilibrium dialysis, in eight kidney transplant patients following their usual oral maintenance dose of prednisone alone and concomitantly with their usual dose of azathioprine. The results showed no significant differences between the two groups in estimates of prednisolone plasma protein binding parameters and peak time, peak concentration, mean input time, clearance/F, volume of distribution/F, or half-life (t 1/2), using total or unbound prednisolone concentrations. Thus, the concomitant administration of azathioprine does not appear to alter the bioavailability or elimination of prednisolone at these doses.