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PubMed1984

Altered plasma protein-binding of prednisolone in patients with the nephrotic syndrome.

Prednisolone binds in plasma to both albumin and transcortin. Since altered concentrations of plasma proteins change capacity and association constants of the drug-protein complex and thus influence the disposition of the drug, the kinetics of prednisolone following oral prednisone and intravenous (IV) prednisolone were studied in ten nephrotic patients and in 12 healthy volunteers. Compared to normal volunteers, nephrotic patients had significantly higher mean (+/- SD) association constants for the albumin-prednisolone complex (4.20 +/- 2.10 X 10(3) M-1 v 2.26 +/- 0.46 X 10(3) M-1, P less than 0.005) and tended to have higher association constants for the transcortin-prednisolone complex. Following the IV administration of prednisolone and the oral administration of prednisone, nephrotic patients exhibited lower total plasma concentrations of prednisolone than did normal volunteers. The difference was attributable to lower albumin-bound and/or transcortin-bound, but not unbound, concentrations of prednisolone in plasma. The mean prednisolone bioavailability from oral prednisone was not different between nephrotic patients and controls. When calculated with reference to total prednisolone concentrations in plasma, the mean nonrenal clearance rate, but not the mean renal clearance rate, was higher in the nephrotic patients than in the controls (2.63 +/- 0.61 mL/min/kg v 1.85 +/- 0.33 mL/min/kg, P less than 0.005). Compared to normal volunteers, patients with the nephrotic syndrome had lower renal clearance rates of unbound prednisolone when prednisolone was given intravenously (1.58 +/- 0.88 mL/min/kg v 2.89 +/- 0.89 mL/min/kg, P less than 0.005) or when prednisone was given orally (1.18 +/- 0.86 mL/min/kg v 2.80 +/- 1.13 mL/min/kg, P less than 0.005). Nephrotic patients had lower ratios of unbound prednisolone clearance/creatinine clearance (fractional excretion) after IV prednisolone (1.50 +/- 0.81 v 2.27 +/- 0.49, P less than 0.025) or after oral prednisone (1.07 +/- 0.60 v 2.12 +/- 0.77, P less than 0.005) than the controls. Since these fractional excretion values of unbound prednisolone exceeded one, there must be glomerular filtration of prednisolone bound to plasma proteins and/or tubular secretion of prednisolone. This study indicates that the nephrotic dysproteinemia changes the binding of prednisolone to plasma proteins not only in point of quantity, but also in point of quality, and alters the disposition of prednisolone.

Administration, Oral↗

PubMed1999

Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression.

In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measured the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin-antithrombin III (TAT) complex following the administration of endotoxin, all of which are associated with DIC, were significantly suppressed by the administration of prednisolone. Heparin administration significantly suppressed changes in all these parameters except for the decrease in platelet count. The combination of prednisolone and heparin was more effective than either treatment alone. In order to determine whether these effects of prednisolone are correlated with the suppression of inflammatory cytokine production, we examined the relationship between changes in plasma levels of cytokine, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induced DIC. Changes in hemostatic parameters associated with DIC following 30 mg/kg per 4 h of endotoxin infusion were significantly suppressed by treatment with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, followed by administration of 250 U/kg heparin 2 h after the start of endotoxin infusion (prednisolone-endotoxin-heparin regimen). The heparin and prednisolone were administrated subcutaneously. The administration of prednisolone and heparin in the reverse order (i.e. heparin first and prednisolone second: heparin-endotoxin-prednisolone regimen) also suppressed changes in hemostatic parameters, albeit to a smaller degree. Cytokine production was also significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of prednisolone alone or heparin alone 30 min before endotoxin significantly reduced the number of renal glomeruli with fibrin thrombi. Plasma levels of creatinine and alanine transferase were reduced only by prednisolone. Increased plasma levels of interleukin-1beta, tissue necrosis factor-alpha and interleukin-6 were suppressed by prednisolone but not by heparin, and there were significant correlations between plasma levels of TAT and cytokines. Prednisolone was more effective than heparin in reducing mortality at 24 h after 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 deaths for prednisolone and heparin, respectively). These findings suggest that prednisolone inhibits the development of endotoxin-induced DIC and reduces mortality by a different mechanism than heparin, possibly through suppressing the production of inflammatory cytokines. Prednisolone may be efficacious in preventing DIC and multiple organ dysfunction caused by endotoxin.

Animals↗

PubMed1982

Prednisolone clearance at steady state in man.

The present study was undertaken to determine whether prednisolone exhibits dose-dependent kinetics in man. Ten normal volunteers were infused to steady state over a 7-h period at a low (5.5 microgram/h . kg) and a high (64 microgram/h . kg) rate with prednisolone. Steady state prednisolone levels differed by a factor of 5 [91 +/- 25 and 437 +/- 116 ng/ml (mean +/- SD)] when the infusion rate was increased 12-fold, indicating a marked increase in the clearance of total prednisolone with increasing dose (the ratio of clearances, high to low dose, was 2.47 +/- 0.29). The fraction of unbound prednisolone increased from 0.12 +/- 0.02 to 0.24 +/- 0.02 with increasing dose. Since the increase in the free fraction (2-fold change) was not as great as the increase in the total prednisolone clearance, there was a slight but significant (P less than 0.05) increase in the apparent clearance of unbound prednisolone (ratio of apparent unbound clearances, high to low dose, was 1.29 +/- 0.24). The interconversion between prednisolone and prednisone appears to approach a maximum prednisone concentration, as was noted previously by us in dogs. In humans, we found this maximum prednisone concentration to be 52 ng/ml when prednisolone is infused. Therefore, the ratio of concentrations, prednisolone to prednisone, also increased with increasing prednisolone dose. These results indicate that prednisolone exhibits dose- and concentration-dependent kinetics and that the great majority of the change in kinetics may be attributed to saturable protein binding of prednisolone. Although there is an increase in the apparent clearance of unbound prednisolone with increasing concentrations, these results are confounded by the interconversion process between prednisone and prednisolone.

Adult↗

PubMed2006

The effect of a single dose prednisolone with and without diclofenac on pain, trismus, and swelling after removal of mandibular third molars.

PURPOSE: The purpose of this study was to evaluate the effect of a single intramuscular dose of prednisolone and the prednisolone-diclofenac combination on postoperative pain, trismus, and edema after the removal of third molars. PATIENTS AND METHODS: Forty-five patients who were to undergo surgical removal of lower third molars were studied. Patients were divided into 3 groups. In the first group, each patient was given 25 mg prednisolone intramuscularly immediately after surgery. In the second group, each patient was given 25 mg prednisolone and diclofenac intramuscularly immediately after surgery, and in the third group, each patient was given sterile saline solution as control group. Postoperative pain was evaluated by visual analogue scale on the day of surgery. Facial swelling and trismus were evaluated on postoperative days 2 and 7. ANOVA was used to analyze these data. RESULTS: Statistical analysis of the data indicated the prednisolone-diclofenac combination suppressed pain intensity in comparison with control (P < .05) at the 6-hour observation. Both the prednisolone and prednisolone-diclofenac combinations suppressed pain at the seventh postoperative hour in comparison with the control (P < .05). The prednisolone-diclofenac combination group also had a smaller loss of opening at postoperative days 2 and 7 in comparison with both the prednisolone and control groups (P < .05). Postoperative swelling was less in both the prednisolone and prednisolone-diclofenac combination groups, as compared with the control group (P < .05) at postoperative day 2. The prednisolone-diclofenac combination group also had a smaller swelling at postoperative day 7 in comparison with both the prednisolone and control groups (P < .05). CONCLUSION: It was determined that the combination of a single dose of prednisolone and diclofenac is well-suited to the treatment of postoperative pain, trismus, and swelling after dental surgical procedures and should be used when extensive postoperative swelling of soft tissue is anticipated.

Adolescent↗

PubMed1984

Alterations in prednisolone disposition as a result of time of administration, gender and dose.

The disposition of total and free prednisolone has been studied in four male and four female volunteers, each of whom received an intravenous dose of 0.075 mg/kg (low) and 1.5 mg/kg (high) of prednisolone at both 06.00 h and 18.00 h. For the low dose, free prednisolone clearance was 14% lower (P = 0.012) and time-averaged prednisolone free fraction was 22% higher (P less than 0.001) in the morning, there being no circadian difference in total prednisolone clearance. There was no circadian differences in prednisolone disposition at the high dose. These findings are consistent with a mechanism in which cortisol causes a simultaneous competitive inhibition of prednisolone clearance and plasma protein binding at low, but not at high prednisolone doses. Prednisolone clearance was higher in female than in male subjects, the mean increase being 18% (P = 0.022) for total prednisolone and 21% (P = 0.036) for free prednisolone. Mean total prednisolone clearance and steady-state distribution volume were two-fold higher at the high vs the low dose (P less than 0.001), but free prednisolone clearance showed a dose dependent decrease of 11% (P = 0.019). There was no change in free prednisolone steady-state distribution volume.

Adult↗

PubMed1990

Clinical pharmacokinetics of prednisone and prednisolone.

The growth of knowledge in the field of the pharmacokinetics of prednisolone/prednisone has been slow for several reasons. First, convenient and specific methods for measuring these steroids only became available with the development of high performance liquid chromatographic methods. Secondly, prednisolone is nonlinearly bound to transcortin and albumin: since the unbound concentrations of prednisolone are biologically relevant, it was necessary to determine the free fraction in each plasma sample. Thirdly, due to the short half-life of prednisolone no steady-state is achieved, and therefore area under the concentration-time curve needed to be determined in all studies. Fourthly, prednisolone and prednisone are interconvertible and prednisolone is given intravenously as an ester prodrug, features which created controversies about the correct interpretation of pharmacokinetic results. Finally, the total body clearances of total and (to a lesser degree) of unbound prednisolone increase with increasing concentrations of prednisolone. Therefore, in order to compare pharmacokinetic results between different subjects, standardised doses had to be administered. The investigations performed so far have revealed that: (1) the dose-dependent pharmacokinetics partly explain the clinical observation that an alternate-day regimen with prednisone yields fewer biological effects; (2) the interconversion of prednisone into prednisolone is not a limiting factor, even in patients with severely impaired liver function; (3) hypoproteinaemia per se does not cause increased unbound concentrations of prednisolone in vivo; (4) patients with liver failure, renal failure or a renal transplant, subjects older than 65 years, women on estrogen-containing oral contraceptive steroids or subjects taking ketoconazole have increased unbound concentrations of prednisolone-whereas hyperthyroid patients, some patients with Crohn's disease, subjects taking microsomal liver enzyme-inducing agents or patients on intravenous prednisolone phthalate (instead of prednisolone phosphate) or on some brands of enteric coated prednisolone tablets have decreased concentrations of prednisolone. The biological relevance of the altered pharmacokinetics is supported in part by altered clinical effects and altered effects on cellular immunofunctions.

Animals↗

PubMed2005

Low-dose prednisolone has a CD4-stabilizing effect in pre-treated HIV-patients during structured therapy interruptions (STI).

BACKGROUND: A favorable development of CD4+ T cells was firstly noticed in therapy-naive HIV-patients without antiretroviral therapy (ART) taking 5 mg prednisolone daily. This observation led to the prescription of prednisolone during structured therapy interruptions (STI). OBJECTIVE: To evaluate the effect of low dose prednisolone on pre-treated patients during STI. METHODS: A retrospective analysis including all pre-treated patients with prednisolone therapy for > or =6 months during STI has been conducted. The patients with prednisolone onset right at the beginning of STI (n = 95) were compared with all patients without prednisolone therapy during their first 6 months of STI (n = 49). Patients with prednisolone were divided into two subgroups: the ongoing STI-group and the patients with ART-restart. Additionally, the development of all 33 patients from the control group having started prednisolone later during STI was documented. Irrespective of the time of initiation of prednisolone therapy during STI, the development of CD4+ T cells in all patients with prednisolone for >12 months during STI was analyzed (n = 108). RESULTS: The mean daily CD4+ T cell decrease during STI was significantly less pronounced in the prednisolone-group (-0.50 vs. -0.74 cells/day; p = 0.0361). The daily CD4+ T cell decline of the 33 patients from the control subgroup including patients with a later onset of prednisolone therapy was only -0.11 during a mean time of 715 days under prednisolone. The CD4+ T cell count of the STI-patients treated with prednisolone for >12 months (n = 108; mean: 837 days +/- 64.6 (366-1,756 days)) decreased from 677/microl to 504/microl. - 51 of 81 patients (63%) included in 2-year-analysis showed stable CD4+ T cell counts (mean daily CD4+ T cell decrease: 0.08) and continued ART interruption. CONCLUSION: This retrospective evaluation provides evidence that low dose corticosteroids are associated with less decrease of CD4+ T cell count in pre-treated HIV patients resulting in prolongation of the potential time of structured treatment interruptions for many HIV patients.

AIDS-Related Opportunistic Infections↗

PubMed2003

Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study.

BACKGROUND: A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent "response" determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV(1)) after prednisolone, and whether the prednisolone response predicts 3 year changes in FEV(1), health status, or number of exacerbations during placebo or fluticasone propionate treatment. METHODS: Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV(1) after prednisolone were investigated using multiple regression. The response to prednisolone was entered into separate mixed effects models of decline in FEV(1) and health status during the 3 years of the study. RESULTS: The post-bronchodilator FEV(1) increased by a mean 60 ml (CI 46 to 74) after prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV(1) after prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p<0.001). There was no relationship between the change in FEV(1) after prednisolone and the response to inhaled bronchodilators, baseline FEV(1), atopic status, age, or sex. The response to prednisolone, however expressed, was unrelated to the subsequent change in FEV(1) over the following 3 years on either placebo or fluticasone propionate. Regression to the mean effects explained much of the apparent prednisolone response. The significant effect of treatment on decline in health status was not predicted by the prednisolone response. CONCLUSION: Patients with COPD cannot be separated into discrete groups of corticosteroid responders and non-responders. Current smoking reduces the FEV(1) response to prednisolone. Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients.

Administration, Oral↗

PubMed1984

Combination effects of Shosaikoto (Chinese traditional medicine) and prednisolone on the anti-inflammatory action.

Effects of combined use of Shosaikoto (one of the famous crude Chinese medicines) and prednisolone were examined in anti-inflammatory effects, using the carrageenan edema and the cotton pellet methods. Shosaikoto and prednisolone were orally given to rats or mice at the dose of 1.1 g/kg (corresponding to 10 times the usual human dose) for the former and 1.0, 4.0 and 16.0 mg/kg for the latter. Shosaikoto showed the mild anti-inflammatory action and significantly increased the anti-inflammatory effect of prednisolone in both experimental models. In cotton pellet method, combined use of Shosaikoto inhibited the decrease of adrenal weight induced by prednisolone. To clarify the mechanism of combined effects of prednisolone and Shosaikoto, the effects of Shosaikoto on the blood prednisolone level and on the secretion of endogenous glucocorticoid (corticosterone) were investigated by high performance liquid chromatography. The blood prednisolone level 20 min after the combined administration of Shosaikoto with prednisolone, 16 mg/kg, was about 2 times comparing with that of single administration of prednisolone. The half life period of blood prednisolone after the single administration of prednisolone was about 2 times comparing with that of the combined administration of Shosaikoto with prednisolone. On the other hand, the single administration of Shosaikoto increased the blood corticosterone level 1 h after the administration with significant manner. The increasing activity of Shosaikoto on the anti-inflammatory effect of prednisolone may be explained by its plural actions.

Adrenal Glands↗

PubMed2005

Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial.

OBJECTIVE: To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis (RA). METHODS: At the start of their initial treatment with a disease-modifying antirheumatic drug (DMARD), patients with early (duration < or =1 year) active RA were randomly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years. Radiographs of the hands and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde. Remission was defined as a Disease Activity Score in 28 joints of <2.6. Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years. RESULTS: Of the 250 patients included, 242 completed the study and 225 had radiographs available both at baseline and at 2 years. At 2 years, the median and interquartile range (IQR) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group (1.8 [IQR 0.5-6.0] versus 3.5 [IQR 0.5-10]; P = 0.019). In the prednisolone group, there were fewer newly eroded joints per patient after 2 years (median 0.5 [IQR 0-2] versus 1.25 [IQR 0-3.25]; P = 0.007). In the prednisolone group, 25.9% of patients had radiographic progression beyond the smallest detectable difference compared with 39.3% of patients in the no-prednisolone group (P = 0.033). At 2 years, 55.5% of patients in the prednisolone group had achieved disease remission, compared with 32.8% of patients in the no-prednisolone group (P = 0.0005). There were few adverse events that led to withdrawal. Bone loss during the 2-year study was similar in the 2 treatment groups. CONCLUSION: Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA, provided a high remission rate, and was well tolerated. Therefore, the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA.

Absorptiometry, Photon↗

PubMed1981

Dose dependent pharmacokinetics of prednisone and prednisolone in man.

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 400 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/1.73 m 2 for the 5 mg dose to 2271 ml/min/1.73 m 2 for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m 2 over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4- to 10-fold over prednisone. In urine, 2-5% of either administered drug was excreted as prednisone and 11-24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.

Adult↗

PubMed2005

Prednisolone augments superoxide formation in porcine pulmonary artery endothelial cells through differential effects on the expression of nitric oxide synthase and NADPH oxidase.

1. Prednisolone, a potent anti-inflammatory drug, has proved ineffective in treating acute respiratory distress syndrome (ARDS). ARDS is associated with superoxide (O(2)(*-)) generation, which negates nitric oxide (NO). NO also downregulates NADPH oxidase and inhibits O(2)(*-) formation. A possible reason for the lack of effect of prednisolone may due to an inhibition of eNOS expression. In order to test this proposal, the effect of prednisolone on O(2)(*-) formation and the expression of gp91(phox) (catalytic subunit of NADPH oxidase) and eNOS in pig pulmonary artery (PA) segments and PA endothelial cells (PAECs) and PA vascular smooth muscle cells (PAVSMCs) was investigated. 2. PA segments and cells were incubated with prednisolone and tumour necrosis factor-alpha (TNF-alpha) for 16 h. O(2)(*-) formation was measured spectrophometrically and gp91(phox) and eNOS expression by Western blotting. The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride, the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ) and the stable cGMP analogues, 8-bromo cGMP and 8-(4-chlorophenylthio)-cGMP (8-pCPT-cGMP). NO release was studied using a fluorescence assay and O(2)(*-)-NO interactions with a nitrite/nitrate assay. 3. Prednisolone elicited significant increase in O(2)(*-) formation in intact PA segments and PAECs, but not PAVSMCs, in a concentration-dependent manner. In endothelium-denuded segments, prednisolone slightly enhanced O(2)(*-) release. TNF-alpha further increased prednisolone-enhanced O(2)(*-) formation in intact PA segments and PAECs. NADPH oxidase inhibitor, apocynin, inhibited O(2)(*-) formation. Increased O(2)(*-) release and gp91(phox) expression in PAECs elicited by prednisolone was blocked by SIN-1 (3-morpholinosydnonimine hydrochloride), DETA-NONOate, 8-pCPT-cGMP and 8-bromo cGMP. The effects of SIN-1 on gp91(phox) expression were reversed by ODQ. Finally, eNOS protein expression was significantly reduced by prednisolone. 4. Prednisolone increases O(2)(*-) in porcine PAECs through a downregulation of endogenous eNOS expression. Since the NO-cGMP axis inhibits gp91(phox) expression, the resultant decrease in endogenous NO formation then augments NADPH oxidase activity, which in turn results in increased O(2)(*-) formation. Since O(2)(*-) promotes inflammation, this mechanism may explain why prednisolone is ineffective in treating ARDS. Therapeutically, the coadministration of an NO donor may render prednisolone more effective in treating ARDS.

Animals↗

PubMed2001

Simultaneous determination of plasma prednisolone, prednisone, and cortisol levels by high-performance liquid chromatography.

Recipients of organ transplants remain particularly dependent on prednisolone as part of their maintenance immunosuppression. Despite this, the pharmacokinetics of prednisolone have never been fully characterized in these patients, and consequently dosing remains empirical. Accurate monitoring of prednisolone, its primary metabolite prednisone, and endogenous cortisol suppression in such patients may provide a means of improving the clinical outcome by adjusting for variability in prednisolone pharmacokinetics and pharmacodynamics. Measurement of endogenous cortisol may provide an independent marker of prednisolone pharmacodynamics. A simple isocratic reverse-phase high-performance liquid chromatography procedure, using betamethasone as an internal standard, was developed to quantify plasma prednisolone, prednisone, and cortisol simultaneously. The steroids were extracted from 0.5 mL plasma with 3 mL (1:1 v/v) ethyl acetate/tert-methyl butyl ether and 0.1 mL phosphoric acid, washed in 0.1 mol/L NaOH before a final drying step and reconstitution in mobile phase for injection. Separation was achieved using a Supelcosil LC-18-DB, 150 x 4.6-mm, 5-microm particle size, reverse-phase column attached to a Newguard 15 x 3-mm, RP8 guard column maintained at 25 degreesC, with ultraviolet detector set at 254 nm. The mobile phase consisted of 16% isopropanol in water containing 0.1% trifluoroacetic acid, set at a flow rate of 1.2 mL/min. The assay was linear up to 1,002 microg/L for prednisolone, 982 microg/L for prednisone, and 545 microg/L for cortisol. Mean intra-assay and interassay imprecision levels were 6.0% and 7.2%, respectively, for prednisolone, 5.8% and 7.2% for prednisone, and 5.6% and 7.9% for cortisol. Intra-assay inaccuracy was <7% of nominal values for prednisolone, prednisone, and cortisol. The lower limit of quantification was 7 microg/L for prednisolone and prednisone and 10 microg/L for cortisol. Corticosteroid recoveries were 73%, 74%, and 90% for prednisolone, prednisone, and cortisol, respectively. The authors describe a robust, inexpensive, and simple method suitable for therapeutic drug monitoring or pharmacokinetic studies of prednisolone; it may also be used to measure the suppression of endogenous cortisol production.

Anti-Inflammatory Agents↗

PubMed1983

The influence of uremia on pharmacokinetics and protein binding of prednisolone.

The pharmacokinetics and protein binding of prednisolone have been compared in 6 uremic patients and 6 healthy controls after intravenous injection of 20 mg prednisolone. The uremic patients had a 53% longer elimination half-time (p less than 0.01) and a 34% larger area under the time-concentration curve (AUC) (p less than 0.05) of total prednisolone than the controls. The total body clearance of total prednisolone was 26% lower and of free prednisolone 40% lower in the uremic patients than in the controls (p less than 0.01). The volume of distribution at steady state was 17% larger in the patients than in the controls, but the difference was not statistically significant. The protein binding of prednisolone was decreased in the patients, the proportion of free prednisolone being 26% higher than in the controls (p less than 0.05). The amount of free prednisolone, expressed as the AUC of free prednisolone, was 67% larger in the patients than in the controls (p less than 0.01). These results indicate that uremic patients taking prednisolone may be more prone to develop glucocorticoid side-effects because of higher concentration of free, biologically active prednisolone, secondary to a reduced rate of elimination and a decreased serum protein binding of prednisolone.

Adult↗

PubMed1984

Alterations in prednisolone disposition as a result of oral contraceptive use and dose.

The disposition of total and free prednisolone has been studied in eight female subjects who used combined oestrogen-progestogen oral contraceptives and in eight female subjects who did not, each of whom received separate intravenous doses of 0.1 mg/kg (low) and 1.0 mg/kg (high) of prednisolone. Mean free prednisolone clearance was reduced congruent to 30% in oral contraceptive users compared to control subjects (P less than 0.001), the difference being greater for the low dose (39%) than for the high dose (24%). Pre-dose plasma cortisol concentrations were elevated two-fold (P less than 0.001) in oral contraceptive users compared to control subjects. These effects are consistent with a mechanism in which the competitive inhibition of free prednisolone clearance by cortisol contributes to the reduction of free prednisolone clearance by oral contraceptive use. Mean total prednisolone clearance and steady state distribution volume showed an approximate two-fold dose dependent increase consistent with a similar increase in plasma prednisolone free fraction (P less than 0.001). Free prednisolone clearance showed an 18% dose dependent decrease (P less than 0.001) but free steady-state distribution volume did not change with dose. At plasma prednisolone concentrations less than 400 ng/ml, prednisolone free fractions at any prednisolone concentration were greater after the low, than after the high dose. This effect is consistent with the displacement of prednisolone by cortisol from transcortin but not from albumin.

Adolescent↗

PubMed1972

Corticosteroids in liver disease: studies on the biological conversion of prednisone to prednisolone and plasma protein binding.

The conversion of prednisone to the biologically active corticosteroid prednisolone and the degree of plasma protein binding of prednisolone were studied in 22 patients with acute or chronic liver disease and in eight control subjects. In patients whose disease was active at the time of study, as judged by elevated serum levels of bilirubin and transaminase, significantly higher levels of plasma prednisolone were obtained after prednisolone administration than after equivalent doses of prednisone. In addition, the amount of unbound drug in the plasma was higher in patients with active disease. There was a significant correlation between the extent of plasma protein binding of prednisolone and the serum albumin concentration. Azathioprine did not affect the plasma binding of prednisolone in vitro. The plasma half-life of prednisolone was prolonged in two of three patients with chronic liver disease studied. These results suggest that in patients with acute hepatitis or active chronic liver disease there is impairment of reduction of the 11-oxo group of prednisone, and also impaired ring A reduction of prednisolone. Thus, incomplete conversion of prednisone to prednisolone occurs, which is a necessary step for biological activity; on the other hand there is also impairment of prednisolone degradation. These, together with low serum albumin concentrations which are associated with higher levels of circulating unbound prednisolone, result in quite different levels of biologically active corticosteroids compared with equivalent doses of prednisone or prednisolone in subjects without liver disease. The findings have important practical implications for the use of corticosteroids in patients with active liver disease.

Adolescent↗

PubMed1992

Pharmacokinetics and pharmacodynamics of prednisolone after intravenous and oral administration.

The pharmacokinetics and pharmacodynamics of prednisolone were investigated according to four different routes of administration: 20 and 40 mg prednisolone orally in the morning, 20 mg prednisolone orally in the evening and 40 mg prednisolone intravenously in form of prednisolone phosphate in the morning. The plasma levels of prednisolone were followed using HPLC. To study the pharmacodynamics of prednisolone, glucose levels and various blood cell parameters such as erythrocytes, leukocytes, segmented neutrophilic granulocytes, eosinophils, basophils, monocytes and lymphocytes were followed. To summarize the data, the area under the effect-time-curve (AUCE) was calculated by the trapezoidal rule. The results show that the pharmacokinetics of prednisolone is dose-dependent (non-linear) and time-dependent. Prednisolone concentrations in plasma after a 20 mg and 40 mg dose are very similar, indicating that the pharmacokinetics of prednisolone are non-linear and dose-dependent with a higher clearance for higher concentrations. The comparison of 20 mg administered in the morning with the same dose given in the evening shows that the pharmacokinetics of prednisolone after oral administration of equal doses changes during the day with higher concentrations in the morning than in the evening. Furthermore, the results of the present study confirm the presence of pharmacodynamic corticosteroid effects on blood cell count and blood glucose. No statistically significant differences were observed for the four different treatments. In summary, it can be concluded that due to the complex pharmacokinetics of prednisolone, it is difficult to make accurate predictions of the expected effect-time relationships.

Administration, Oral↗

PubMed1987

Impairment of prednisolone metabolism by cyclosporine treatment in renal graft recipients.

Pharmacokinetics of prednisolone were studied in 64 randomly chosen renal transplant patients treated with azathioprine and prednisolone (Aza-Po) or cyclosporine and prednisolone (CsA-Po). Intrinsic clearance for prednisolone was calculated after an oral test dose of 0.5 mg prednisolone/kg bodyweight. In 38 patients on Aza-Po treatment the mean clearance for prednisolone was 0.17 +/- 0.04 1/kg/hr (range 0.11-0.27) and in 39 patients on CsA-Po the mean prednisolone clearance was 0.12 +/- 0.02 (0.07-0.17) (P less than 0.001). Eight patients on CsA-Po were tested on three occasions; prednisolone clearance at 2-4 weeks was 0.13 +/- 0.02 (range 0.11-0.17), at 3-6 months 0.11 +/- 0.01 (0.10-0.12) and at 2-5 years 0.11 +/- 0.02 (0.09-0.14). In 11 patients the treatment was changed from Aza-Po to CsA-Po. The prednisolone clearance then decreased from 0.18 +/- 0.05 1/kg/hr (range 0.13-0.27) to 0.12 +/- 0.03 (0.10-0.16) (P less than 0.001). When the treatment was changed from CsA-Po to Aza-Po in 2 patients the prednisolone clearance increased from 0.12 and 0.10 to 0.17 and 0.12 1/kg/hr, respectively. These data show not only that the prednisolone metabolism is slower in cyclosporine-treated patients but also that this metabolism is retarded when azathioprine is replaced by cyclosporine, and that it is accelerated when cyclosporine is replaced by azathioprine. In the CsA-Po treated patients the prednisolone clearance was also found to be lower after 3-6 months than after less than one month (P less than 0.05) but there has been no further decrease in the prednisolone metabolism after up to more than 4 years of cyclosporine treatment.

Adolescent↗