Protein Binding Of Prednisolone Research Articles

The separation of unbound prednisolone in plasma by centrifugal ultrafiltration.

To study variable plasma protein binding of prednisolone in children with nephrotic syndrome we have devised a simple rapid method for measuring unbound prednisolone. The plasma was initially ultrafiltered at 37 degrees C fixed angle head at 1500 g for 30 min then the filtrate was analysed by high pressure liquid chromatography. The effects of variable ultrafiltration conditions were studied. The method was used to compare the AUC unbound prednisolone in a nephrotic child (plasma albumin concentration 18 g L-1) with a control (plasma albumin concentration 43 g L-1); their respective AUC unbound prednisolone values were 4.02 mg h L-1 and 1.07 mg h L-1.

A Pharmacokinetic/Pharmacodynamic Approach to Predict Total Prednisolone Concentrations in Human Plasma

Prednisolone and prednisone are two widely used corticosteroids for various inflammatory and immune diseases. Prednisolone is the active form of prednisone in vivo. Total prednisolone in plasma exhibits nonlinear pharmacokinetics mainly due to its nonlinear protein binding. Other factors such as reversible metabolism (or interconversion between prednisolone and prednisone), competitive protein binding from endogenous cortisol, cortisol circadian rhythm, and prednisolone mediated cortisol suppression complicate prednisolone pharmacokinetics. This study was aimed to develop a new approach to describe the nonlinear pharmacokinetics of total prednisolone and predict total prednisolone concentrations in plasma. Based on literature datasets, a linear two-compartment pharmacokinetic model was developed to adequately describe the reversible metabolism between free prednisone and prednisolone. Cortisol and prednisolone protein binding were described via the sum of a Langmuir and linear type binding. The endogenous cortisol circadian rhythm and cortisol suppression during prednisone or prednisolone exposure were described with a previously reported linear release rate pharmacokinetic/pharmacodynamic (PK/PD) model. By combining the pharmacokinetic models for free prednisone and prednisolone, the linear release rate model for cortisol suppression, and competitive protein binding between cortisol and prednisolone, we were able to predict total prednisolone concentrations in plasma. The predicted total prednisolone concentrations in plasma were in good agreement with the literature reported data. Thus, this PK/PD approach shows that the combination of nonlinear protein binding, cortisol circadian rhythm, and cortisol suppression could account for the nonlinearity of total prednisolone. In addition, it also allows a valid prediction of total prednisolone in plasma after either prednisone or prednisolone administration.

Intraocular penetration kinetics of prednisolone after subconjunctival injection in rabbits.

Prednisolone concentrations in cornea, aqueous humor, and vitreous humor and the residual amount in conjunctival tissue were assayed by high-performance liquid chromatography during a 14-hour period after subconjunctival injection of prednisolone sodium succinate in rabbits. Prednisolone was concentrated in the corneal epithelium and reached a peak within 5 min, whereas the peak level of prednisolone in stroma-endothelium was achieved 1 h after the injection. There was an apparent linear binding of prednisolone with the ocular tissue homogenates and fluids except for the vitreous humor. However, the protein binding of prednisolone with vitreous humor showed marked concentration dependency. A pharmacokinetic model involving a rapid conversion to prednisolone from its ester prodrug, first-order transfer to various tissues, and first-order elimination of unbound prednisolone from vitreous humor succeeded in predicting the observed concentration-time profiles of prednisolone in various ocular tissues and fluids after subconjunctival injection at three different doses: 0.1, 1.0, and 10.0 mg/kg. The present model predicted that absorption into precorneal area and epithelium and direct penetration into aqueous humor and vitreous humor are 1.7, 0.1, and 0.2% of the applied dose, respectively, and that almost the entire dose (98%) is absorbed into the systemic circulation, with a half-life of 38 min.

Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia.

The disposition of the synthetic corticosteroids, dexamethasone and prednisolone, in CSF was evaluated following bolus intravenous (IV) and intrathecal (IT) injection in a nonhuman primate model. Steroid concentration in plasma and CSF was measured with a radioimmunoassay following celite column chromatography. The CSF to plasma ratios of dexamethasone and prednisolone following IV bolus administration were 0.15 +/- 0.02 and 0.08 +/- 0.03, respectively. Although peak levels of the two steroids in the CSF reached equally potent levels when administered systemically in equipotent doses, the half-life of prednisolone in the CSF was shorter. In addition, there was a significant difference in the plasma protein binding of the two steroids, which may account for the differences in their CSF pharmacokinetics. Dexamethasone was 70% protein bound over a wide concentration range, while the protein binding of prednisolone was concentration dependent, ranging from 60% at 10 mumol/L to 95% at 0.5 mumol/L and below. After the initial distribution phase in plasma, CSF concentrations of dexamethasone and prednisolone approximated free plasma concentrations, indicating that penetration into the CSF was limited primarily by protein binding. At the plasma concentrations achieved following oral administration of standard doses of prednisone in children, the prednisolone (the active metabolite) is greater than 90% protein bound. The proportionally higher free plasma levels of dexamethasone result in greater penetration into the CSF. These findings may explain the lower rates of meningeal leukemia observed in children receiving dexamethasone instead of prednisone for the treatment of acute lymphoblastic leukemia (ALL).

Dose-dependent pharmacokinetics of prednisolone in normal and adrenalectomized rats.

The pharmacokinetics of prednisolone after 5- and 50-mg/kg doses given as the sodium succinate salt was examined in normal and adrenalectomized rats. Prednisolone, prednisone, and corticosterone concentrations in plasma were determined by HPLC and free prednisolone measured by equilibrium dialysis. Prednisolone sodium succinate was rapidly and completely hydrolyzed to prednisolone as indicated by the absence of the ester from plasma within 5 min after intravenous injection. Prednisolone was rapidly metabolized to prednisone, while corticosterone concentrations in normal rats declined rapidly and were undetectable by 1 hr. Adrenalectomy had no effect on the disposition and protein binding of prednisolone. Dose, however, had a marked effect on prednisolone pharmacokinetics, with mean plasma clearance decreasing from 6.18 to 3.07 L/h per kg and mean steady-state volume of distribution decreasing from 2.14 to 1.05 L/kg from the lower to higher steroid dose. Half-life (0.50 hr) and mean residence time (0.35 hr) were unaffected by dose. Prednisolone plasma protein binding was nonlinear due to saturation of transcortin binding. Changes in pharmacokinetic parameters were not related to the nonlinear plasma binding, but were more likely caused by saturation of elimination pathways and tissue binding sites.

Prednisolone protein binding in renal transplant patients.

Prednisolone pharmacokinetics and protein binding characteristics were studied in 10 renal transplant patients with various degrees of renal function (serum creatinine: 80-380 mumol/l) who received their usual oral maintenance dose of prednisolone (0.18 +/- 0.04 mg/kg). Plasma was assayed for prednisolone and hydrocortisone by h.p.l.c. and free prednisolone concentrations were determined in each sample by a rapid ultrafiltration technique. Free prednisolone area under curve (AUCu) ranged from 101 to 436 ng ml-1 h and was 6.3 to 15.0% of total prednisolone AUC. The fraction AUCu/AUC was closely related to serum albumin and creatinine concentrations determined at the time of study (multilinear regression correlation coefficient r2 = 0.830, P less than 0.0001); elevated serum creatinine and low albumin concentrations were associated with a higher % free. These results suggest that much of the variability in prednisolone protein binding could be attributed to inter-patient variability in serum albumin and creatinine concentrations. Total prednisolone concentrations would be potentially misleading in any comparisons made between patient groups with different renal function.

The Effect of Altered Prednisolone Kinetics in Patients with the Nephrotic Syndrome and in Women Taking Oral Contraceptive Steroids on Human Mixed Lymphocyte Cultures

The purpose of this study was to examine the influence of altered prednisolone kinetics in patients with the nephrotic syndrome and women taking oral contraceptive steroids on mixed lymphocyte cultures (MLC). After oral and iv prednisolone treatment, blood samples were collected over 24 h. The area under the plasma concentration vs. time curve (AUC) of unbound, transcortin- bound, and albumin-bound prednisolone was determined. All plasma samples were incubated with MLCs, and the area under the inhibition vs. time curve of the MLC (AUIC), a measure of the effect over time, was calculated. The steroid concentrations required to produce half-maximal inhibition (EC50) were calculated. The 10 women taking oral contraceptives had higher AUCs of unbound and transcortin-bound prednisolone than the 10 normal subjects. The mean biological effect (AUIC value) was more pronounced in women taking contraceptive steroids. An analysis of the concentration-response curves revealed that the EC50 values of total, but not unbound, prednisolone were higher in women taking contraceptives. Compared with the normal subjects, the 9 nephrotic patients had lower total and comparable unbound AUCs of prednisolone. The AUIC values were higher whereas the EC50 values of unbound and total prednisolone were lower in the nephrotic patients. These findings indicate that the increased steroid effect in women taking oral contraceptives is explained by higher concentrations of prednisolone, while the increased effect in nephrotic patients is not attributable to the abnormal kinetics or protein binding of prednisolone.

Pharmacokinetics and protein binding of prednisolone in patients with nephrotic syndrome and patients undergoing hemodialysis

Pharmacokinetics and protein binding of prednisolone in patients with nephrotic syndrome and patients undergoing hemodialysis. Pharmacokinetics and protein binding of intravenously administered prednisolone were studied in seven patients with nephrotic syndrome and normal serum creatinine, seven patients with chronic renal failure undergoing hemodialysis, and 12 healthy control subjects. Compared to the control subjects, the patients with nephrotic syndrome had a 24% lower peak prednisolone serum concentration (P Pharmacocinetique et liaison proteique de la prednisolone chez des malades atteints de syndrome nephrotique et des malades en hemodialyse. La pharmacocinetique et la liaison proteique de la prednisolone administree par voie intra-veineuse ont ete etudiees chez sept malades atteints de syndrome nephrotique et avec une creatinine serique normale, sept malades atteints d'insuffisance renale chronique en hemodialyse, et 12 sujets controles sains. Par rapport aux subjets controles, les malades atteints de syndrome nephrotique avaient un pic de concentration serique de prednisolone plus faible de 24% (P

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.

Altered prednisolone pharmacokinetics in patients treated with rifampicin.

The pharmacokinetics and protein binding of prednisolone were studied in 7 patients before and after 3 weeks of rifampicin therapy. The elimination half-time for prednisolone decreased by 45 +/- 8.1% (p less than 0.01), and the total body clearance of prednisolone increased by 91 +/- 26% (p less than 0.01). The area under the time-concentration curve (AUC) of total (free plus protein-bound) prednisolone decreased by 48 +/- 7.3% (p less than 0.01) and of free, unbound prednisolone by 57 +/- 9.8% (p less than 0.01). The reduction in AUC was greater for free than for total prednisolone (p less than 0.05) mainly due to the non-linear nature of prednisolone protein binding. There was no significant change in the volume of distribution. Because of the marked reduction in total and especially free prednisolone, the dosage should be adjusted accordingly if prednisolone and rifampicin are prescribed concomitantly.

Pharmacokinetics and protein binding of prednisolone after oral and intravenous administration.

The pharmacokinetics of prednisolone after oral and intravenous administration of 10 and 20 mg have been studied. Serum protein binding of prednisolone was also measured after the i.v. injections. The bioavailability after oral administration was 84.5% after 10 mg and 77.6% after 20 mg (p greater than 0.05). Dose dependent pharmacokinetics were found, the VDss and Clt being significantly larger (p less than 0.01) after 20 mg i.v. than after 10 mg i.v. The protein binding of prednisolone in all subjects was non-linear, and is the most likely cause of the dose dependent pharmacokinetics, as there was no dose dependent variation in elimination half-time.

Prednisolone binding to albumin and transcortin in the presence of cortisol

The protein binding of prednisolone was assessed in a 5% albumin solution and in pooled human serum, alone and in the presence of various amounts of cortisol. Significant displacement of prednisolone from transcortin binding sites occurred with little or no change in transcortin binding capacity or affinity constant for prednisolone, suggesting competitive inhibition of prednisolone binding by cortisol. Little or no displacement of prednisolone from the protein binding sites on albumin occurred though a decrease in the number of binding sites (four vs two), and an increase in the affinity constant for the albumin-prednisolone interaction (4.32 × 10 2 vs 9.43 × 10 2 M̄ −1) occurred in the presence of cortisol. Allosteric or conformational changes may occur in albumin structure in the presence of cortisol. These alterations have no effect on the fraction of prednisolone bound to albumin.

Studies Comparing the Metabolic Clearance Rate of 11β,17,21-Trihydroxypregn-1,4-Diene-3,20-Dione (Prednisolone) after Oral 17,21-Dihydroxypregn-l,4-Diene-3,11,20-Trione and Intravenous Prednisolone

The MCR of prednisolone (11 beta,17,21-trihydroxypregn-1,4-diene-3,20-dione) and the absorption of prednisone (17,21-dihydroxypregn 1,4-diene-3,11,20-trione) were studied in five normal subjects and four patients. Plasma and urinary prednisolone were measured by a competitive radioassay. The MCR was determined after iv administration of 30 mg nonisotopic prednisolone using one-compartment (MCR1) and two-compartment (MCR2) analyses. These values were compared with the MCR determined after oral administration of nonisotopic prednisone (MCR0). MCR1 and MCR2 were closely correlated, indicating the applicability of first order kinetics to the study of prednisolone metabolism. In subjects with normal gastrointestinal function, MCR0 was consistently lower than MCR2 (mean MCR2 = 0.175 liters/h.kg; MCR0 = 0.145 liters/h.kg). In two patients with steroid malabsorption, the MCR0 was significantly greater than MCR2. Knowledge of the expected relationship between MCR0 and MCR2 allowed quantitation of the degree of malabsorption. With or without impaired absorption, the absorptive process was essentially complete by the time of the peak plasma concentration. Estrogen therapy lowered the MCR0, and high prednisone dose increased the MCR0. Those effects and the effects of iv prednisolone administration on the MCR are explained by the effects of plasma protein binding of prednisolone. These studies demonstrate the usefulness of the oral MCR determination in the evaluation of steroid absorption and metabolism.