Plasma Prednisolone Concentrations Research Articles

Prednisolone and dexamethasone are systemically absorbed after topical application of ophthalmic suspensions in healthy dogs.

To quantify plasma concentrations of prednisolone and dexamethasone (peripheral and jugular) and cortisol following topical ophthalmic application of 1% prednisolone acetate and 0.1% dexamethasone to healthy adult dogs. 12 purpose-bred Beagles. Dogs received 1 drop of 1% prednisolone acetate (n = 6) or neomycin polymyxin B dexamethasone (ie, 0.1% dexamethasone; 6) ophthalmic suspension in both eyes every 6 hours for 14 days. Blood samples (peripheral and jugular) were collected on days 0, 1, 7, and 14 and analyzed for plasma prednisolone and dexamethasone concentrations. Plasma cortisol concentrations were measured at the beginning of the study and following topical drug administration. Both drugs demonstrated systemic absorption. Prednisolone was detected on days 1, 7, and 14 (median plasma concentration, 24.80 ng/mL; range, 6.20 to 74.00 ng/mL), and dexamethasone was detected on days 1, 7, and 14 (2.30 ng/mL; 0 to 17.70 ng/mL). Neither prednisolone nor dexamethasone were detected in plasma samples on day 0 (baseline). Sampling from the jugular vein resulted in higher plasma drug concentrations than from a peripheral vein when samples from each day were combined. Plasma cortisol concentrations were significantly lower than baseline following 14 days of treatment with topical prednisolone acetate and dexamethasone. Prednisolone and dexamethasone are detected in the plasma of healthy dogs following topical ophthalmic administration 4 times/d with prednisolone concentrations being close to a physiologic dose of orally administered prednisolone. Additional research is needed to evaluate the systemic absorption of these medications in dogs with ocular inflammation.

Prednisolone Concentrations in Plasma (Total and Unbound) and Saliva of Adult Kidney Transplant Recipients.

Prednisolone displays significant pharmacokinetic variability and exposure-outcome relationships in renal transplant recipients, suggesting a role for drug monitoring in some scenarios. It is highly protein-bound, and the free form is pharmacologically active but cumbersome to measure. Saliva concentrations might reflect free plasma prednisolone and present an alternative measurement. The aim of this study was to examine the correlation between total and free plasma and saliva prednisolone in adult renal transplant recipients. Total and free plasma and saliva prednisolone concentrations were measured in 20 patients receiving oral prednisolone 1-2 months after transplant, between pre-dose and 12 hours post-dose. Prednisolone was determined using high-performance liquid chromatography mass spectrometric detection. The Pearson coefficient was used to assess the association between plasma and salivary prednisolone concentrations and area under the concentration-time curves (AUC0-12). When considering all time points, the total and free plasma prednisolone concentrations correlated well (r = 0.81), but there was poor correlation between saliva and free (r = 0.003) and total (r = 0.01) plasma concentrations. When concentrations before the maximum free prednisolone plasma value were excluded, the correlation between free plasma and saliva concentrations improved (r = 0.57). There was a moderate correlation between free and total plasma prednisolone AUC0-12 (r = 0.62) using all time points, but a poor correlation between free and total plasma prednisolone AUC0-12 and saliva AUC0-12 (r = 0.07; r = 0.17). Total and free plasma prednisolone measurements correlated poorly with saliva measurements; however, correlation improved when concentrations early in the dosing interval were excluded.

Free prednisolone pharmacokinetics predicted from total concentrations in patients with inflammatory - immunonologic conditions.

Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CLU /F and VU /F, scaled allometrically on lean body weight, were, respectively, 26.7L/h and 94.3L for 50kg LBW. CLU /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.

Emergency treatment of adrenal crisis with prednisone suppositories: a bioequivalence study in female patients with Addison's disease.

ObjectivePatients with adrenal insufficiency (AI) need to adapt their glucocorticoid replacement under stressful conditions to prevent adrenal crisis (AC). Prednisone (PN) suppositories are used for emergency treatment. Pharmacokinetics of 100 mg PN suppositories after vaginal or rectal administration was evaluated.DesignSingle-center, open-label, sequence-randomized, cross-over, bioequivalence study.MethodsTwelve females with primary AI were included. Comparison of pharmacokinetics after vaginal and rectal administration of 100 mg PN suppositories. Main outcome measures: bioequivalence (Cmax: maximum plasma concentration of prednisolone; AUC0 –360: area under the plasma concentration curve of prednisolone from administration to 360 min), adrenocorticotropin (ACTH) levels, safety and tolerability. Comparison of ACTH-suppressive effect with subcutaneous and intramuscular administration of 100 mg hydrocortisone.ResultsVaginal administration of PN suppositories was not bioequivalent to rectal administration: Cmax and AUC0–360 were significantly lower after vaginal compared to rectal administration: 22 ng/mL (109%) vs 161 ng/mL (28%), P < 0.001; 4390 ng/mL * min (116%) vs 40,302 ng/mL * min (26%), P < 0.001; (mean (coefficient of variation), respectively). A suppression of ACTH by >50% of baseline values was observed 149 min (32%) after rectal PN administration; after vaginal PN administration, the maximum decrease within 360 min was only 44%. Adverse events were more frequent after vaginal administration and mainly attributable to the glucocorticoid deficit due to inadequate vaginal absorption. The ACTH-suppressive effect was more pronounced after parenteral hydrocortisone compared to rectal or vaginal PN.ConclusionVaginal administration of PN suppositories in the available form is not useful for prevention of AC. Pharmacokinetics after rectal use of PN show inferiority compared to available data on parenteral glucocorticoids. In adrenal emergencies, hydrocortisone injection should be the first choice.

PH-sensitive polymeric micelles for targeted delivery to inflamed joints

Effective treatment for rheumatoid arthritis is hindered by the lack of drugs that selectively target inflamed joints. Liposomes, nanoparticles and conventional micelles loaded with limited amounts of drugs may be unstable in the circulation and result in uncontrolled drug release kinetics. Here we developed a new drug delivery system of pH-sensitive polymeric micelles based on an acid-labile hydrazone bond. Amphiphilic conjugates of a PEG-based derivative and the hydrophobic drug prednisolone (PD) self-assembled into PD micelles with a drug loading of 19.29%. When the micelles reached the acidic environment of synovial fluid, the hydrazone bonds hydrolyzed, releasing free PD. Intravenous injection of PD micelles into mice with collagen-induced arthritis led to PD accumulation in affected joint tissues. PD concentrations in plasma and joints of arthritic mice were significantly higher after injection with PD micelles than after injection with free PD. The enhancement effect in joints was 4.63-fold based on the area under the concentration-time curve and 2.50-fold based on the maximum concentration (Cmax). In vivo pharmacodynamics experiments showed PD micelles to have better anti-inflammatory and disease-modifying effects than free PD. Our results indicate the promise of PD micelles for targeted drug delivery in inflammatory disease.

Exploratory study of total and free prednisolone plasma exposure and cushingoid appearance, quality of life and biochemical toxicity in adult male kidney transplant recipients.

Long-term adverse effects of oral glucocorticoids are frequent and serious. Large between-patient variability in the pharmacokinetics of prednisolone might explain why drug dose is a poor predictor of drug-related toxicity. The aim of the study was to investigate relationships between prednisolone exposure and adverse effects. Male kidney transplant recipients were recruited for serial blood sampling and assessment of glucocorticoid-related adverse effects including dyslipidaemia, abnormal body fat distribution, Cushingoid appearance and impaired quality of life. Total and free prednisolone plasma concentrations were determined using ultra-high-performance liquid chromatography with tandem mass spectrometric detection. Prednisolone exposure was estimated using a limited sampling strategy. Fifty-six patients were recruited. Patients had a mean age of 54 years and median time post-transplantation of 75 months. Median prednisolone dose was 5 mg. Mean area under the plasma concentration-time curve was 2390 nmol h/L (±580) (SD) and 175 nmol h/L (±78) for total and free prednisolone, respectively. Waist to upper arm circumference ratio was positively associated with free prednisolone plasma exposure with a Spearman correlation coefficient of 0.30 (p value 0.02). The correlation coefficient was 0.24 (p value 0.08) for neck to upper arm circumference ratio and free prednisolone plasma exposure. The clinical Cushingoid phenotype as determined by the Visual Assessment of Cushing's Severity (VACS) score was associated with a reduced score relating to physical functioning on the SF-12, but there was no significant relationship between free prednisolone plasma exposure and quality-of-life scores. Lipid levels and haemoglobin A1c (HbA1c) were not associated with total or free prednisolone exposure. There is a positive correlation between free prednisolone plasma exposure and waist to upper arm circumference ratio in adult male kidney transplant recipients on low maintenance prednisolone doses. There is no significant association between total or free prednisolone plasma exposure and plasma glucose and lipid levels in the low prednisolone dose range.

Plasma, blood and liver tissue sample preparation methods for the separate quantification of liposomal-encapsulated prednisolone phosphate and non-encapsulated prednisolone

Besides the development of sample preparation methods for the determination of separate liposomal-encapsulated prednisolone phosphate and non-encapsulated prednisolone concentrations in murine plasma and blood, this article also presents the first description of an accurate sample preparation method for the determination of such separate concentrations in the murine liver. The quantitative differentiation is based on the immediate hydrolysis of prednisolone phosphate (PP) into prednisolone (P) after its release from the liposomes in vivo: PP represents the encapsulated drug, while P represents the non-encapsulated drug. The use of 10 ml methanol/g tissue during homogenization of liver tissue ensures complete liposome rupture, prevention of the dephosphorylation of PP released during homogenization, sufficient clean supernatants, excellent extraction of P and sufficient extraction of PP and excellent accuracies and precision complying with the internal guidelines for pre-clinical studies (80–120% and maximal 20%, respectively). Similarly, the matching sample preparation methods for plasma and blood involve protein precipitation with four equivalents of methanol also ensuring accuracies and precision complying with the internal guidelines for pre-clinical studies. Application of these sample preparation methods is going to generate the first pharmacokinetic (PK) profile of a liposomal preparation, in which the encapsulated and non-encapsulated drug concentrations in a tissue are measured separately. Such separated concentration profiles can gain important insights into the PKs of liposomal PP and probably also with regard to liposomal formulations in general, like the quantification of the in vivo drug release from the liposomes.

Comparison of the Influence of Cyclosporine and Tacrolimus on the Pharmacokinetics of Prednisolone in Adult Male Kidney Transplant Recipients

Cyclosporine has been observed to precipitate cushingoid features in kidney transplant recipients already on prednisolone. Some pharmacokinetic studies have demonstrated increased prednisolone exposure in patients on cyclosporine therapy compared with azathioprine, whereas other studies have found no difference. The objective of this study was to determine whether cyclosporine impacts on prednisolone exposure as compared with tacrolimus. Adult male kidney transplant recipients treated with prednisolone and either cyclosporine or tacrolimus were recruited for pharmacokinetic blood sampling at the outpatient clinic at the Princess Alexandra Hospital, Brisbane, Australia. Prednisolone plasma concentrations were determined using ultra-high-performance liquid chromatography. Dose-adjusted area under the plasma concentration-time curve (AUC) of free and total prednisolone was estimated using a previously developed limited sampling strategy and non-compartmental analysis. A total of 55 patients were eligible for analysis; 38 % received cyclosporine and 62 % received tacrolimus co-therapy. No significant difference in mean dose-adjusted total prednisolone AUC from 0 to 6 h post-dose or mean dose-adjusted free prednisolone AUC from 0 to 12 h was observed between the cyclosporine and tacrolimus groups (449 versus 428 nmol·h/L/mg, p = 0.43, and 32 versus 30 nmol·h/L/mg, p = 0.51, respectively). Cyclosporine does not change the dose-adjusted exposure of prednisolone compared with tacrolimus. Adult kidney transplant recipients can therefore continue on their usual prednisolone dose when changing therapy between cyclosporine and tacrolimus.

Effect of Eclipta prostrata on 11Beta-Hydroxysteroid Dehydrogenase in Rat Liver and Kidney.

Eclipta prostrata (EP) is often prescribed in combination with glucocorticoid to treat glomerular nephritis, nephrotic syndrome, and IgA nephropathy in clinical practice of Traditional Chinese Medicine. Previous studies from our laboratory revealed that coadministration of EP significantly increased the plasma concentration of prednisolone while decreased the level of cotreated prednisone in rats. However, the underlying mechanism remains unclear. 11β-Hydroxysteroid dehydrogenase (11β-HSD) belongs to the family of oxidoreductases that catalyze the interconversion of prednisone to active prednisolone. Therefore, the current study aimed to investigate the effects of EP on the activity and expression of 11β-HSD in rat liver and kidney. The results showed that oral administration of EP significantly increased the activity of 11β-HSD I in the liver and 11β-HSD II in the kidney by employing the microsomal incubation system. Moreover, gene and protein expressions of 11β-HSD I and 11β-HSD II were also increased in rat liver and kidney, respectively. These results suggest that the effects of EP on 11β-HSD may attribute to the mechanism that administration of EP improves the efficacy and reduces adverse drug reactions of glucocorticoid in patients undergoing combinational therapy.

Interactions of Abiraterone, Eplerenone, and Prednisolone with Wild-Type and Mutant Androgen Receptor: A Rationale for Increasing Abiraterone Exposure or Combining with MDV3100—Letter

We read with interest the report from Richards and colleagues (1) on the potential interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor (AR). Abiraterone is a CYP17A1 inhibitor that blocks androgen biosynthesis in the testes, adrenals, and castration-resistant prostate cancer (CRPC) tumors, producing androgen ablation with significant clinical benefit in patients with metastatic CRPC. The current report (1) and other studies (2) suggesting that abiraterone downregulates AR expression and produces antiandrogen activity beyond androgen depletion merit further investigation.The suppression of adrenal steroid biosynthesis via abiraterone inhibition of CYP17A1 reduces circulating cortisol, with compensatory release of adrenocorticotropic hormone (3). This induces increased adrenal secretion of mineralocorticoids that can contribute to hypokalemia and hypertension. These manifestations of mineralocorticoid excess are managed by coadministration of low-dose prednisone (a prodrug of prednisolone) in patients treated with abiraterone acetate.Richards and colleagues reported that prednisolone activated the AR in cells transfected with T877A-mutant AR with an EC50 of 25.1 μmol/L. This suggested that coadministration of prednisolone with abiraterone acetate could contribute to disease progression. However, the EC50 is much higher than the plasma concentrations of prednisolone (4–305 nmol/L) measured in 15 patients with CRPC receiving abiraterone acetate plus prednisolone. Furthermore, the authors extrapolated the reported prednisolone plasma concentrations to a prior publication on the in vitro androgen agonist activity of glucocorticoids at nanomolar concentrations in a cell line bearing an AR ligand-binding domain double mutation (T877A plus L701H) to ascribe clinical significance (4). We feel that this comparison is inappropriate in relation to the current findings and the interpretation of the findings related to abiraterone acetate therapy. The prevalence of this double mutation is unknown without established clinical relevance.The authors also reported findings using spironolactone and eplerenone, which produced androgen agonist activity in vitro in cells transfected with wild-type (spironolactone only) or mutant AR at concentrations relevant to clinical activity. The report suggested that this could contribute to disease progression if these drugs were used in patients with prostate cancer. However, neither agent is proposed for use with abiraterone acetate to ameliorate symptoms of mineralocorticoid excess.Abiraterone acetate was studied in conjunction with low-dose prednisone/prednisolone in registration trials leading to approval (5); only prednisone/prednisolone, not spironolactone or eplerenone, are specified in approved labeling. Given the high concentrations of prednisolone investigated in the reported in vitro studies, the clinical significance of the findings is not obvious.D. End is employed as Director of Johnson and Johnson/Janssen and has ownership interest (including patents) in Johnson and Johnson. A. Molina is the Vice President of Johnson and Johnson and has ownership interest (including patents) in the stock options of Johnson and Johnson. No potential conflicts of interest were disclosed by the other authors.

Influence of body condition on plasma prednisolone and prednisone concentrations in clinically healthy cats after single oral dose administration

Influence of body condition (over-conditioned vs. normal-conditioned) on plasma glucocorticoid concentrations after single dose oral prednisolone or prednisone in 11 cats (5 normal-conditioned and 6-over-conditioned) was investigated using a two-drug crossover trial (3-week washout interval). Body condition was determined using criterion-referenced bioelectrical impedance together with plasma drug concentrations (prednisolone [active drug] and prednisone [pro-drug]) measured by HPLC. Although interconversion of each drug to the other was confirmed, a single 2mg/kg body weight oral dose of prednisolone produced significantly higher plasma prednisolone concentration (∼4-fold higher AUC) compared to prednisone. Significantly higher plasma drug concentrations in over-conditioned cats (∼2-fold) compared to normal-conditioned cats might explain their perceived increased risk for glucocorticoid associated side effects (hepatic lipidosis, diabetes mellitus). Findings suggest low comparative bioavailability of oral prednisone compared to prednisolone in cats and consideration of lean body mass or ideal body weight for dosing practices.

Plasma and Ocular Prednisolone Disposition after Oral Treatment in Cats

Objective. To evaluate the plasma and aqueous humor disposition of prednisolone after oral administration in cats. Methods. Six cats were administered with a single oral dose of prednisolone (10 mg). Blood and aqueous humor samples were serially collected after drug administration. Prednisolone concentrations in plasma and aqueous humor were measured at 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, and 5.0 h after administration by a high-performance liquid chromatographic analytical method developed and validated for this purpose. Results. Mean ± standard error (SE) of maximum plasma prednisolone concentration (300.8 ± 67.3 ng/mL) was reached at 1 h after administration. Prednisolone was distributed to the aqueous humor reaching a mean peak concentration of 100.9 ± 25.5 ng/mL at 1.25 h after administration. The mean ± SE systemic and aqueous humor exposure (AUC) was 553.3 ± 120.0 ng∗h/mL and 378.8 ± 64.9 ng∗h/mL, respectively. A high AUCaqueous humor/AUCplasma ratio was observed (0.68 ± 0.13). The mean half-life time of elimination in plasma and aqueous humor was 0.87 ± 0.16 h and 2.25 ± 0.44 h, respectively. Clinical Significance. The observed high ratio between aqueous humor and plasma prednisolone concentrations indicates that extensive penetration of prednisolone to the anterior segment of the eye may occur. This is the first step that contributes to the optimization of the pharmacological therapeutics for the clinical treatment of uveitis.

Influence of P-glycoprotein modulation on plasma concentrations and pharmacokinetics of orally administered prednisolone in dogs

To evaluate the impact of modulation of the membrane-bound efflux pump P-glycoprotein (P-gp) on plasma concentrations of orally administered prednisolone in dogs. 7 healthy adult Beagles. Each dog received 3 treatments (control [no treatment], rifampicin [100 mg/d, PO, for 21 days, as an inducer of P-gp], and ketoconazole [100 mg/d, PO, for 21 days, as an inhibitor of P-gp]). A single dose of prednisolone (1 mg/kg, PO) was administered on day 8 of each treatment period. There was a 7-day washout period between subsequent treatments. Plasma concentrations of prednisolone were determined by use of a validated liquid chromatography-tandem mass spectrometry method. Duodenum and colon biopsy specimens were obtained endoscopically from anesthetized dogs and assessed for P-gp protein labeling via immunohistochemical analysis and mRNA quantification via real-time PCR assay. Total fecal collection was performed for evaluation of effects of P-gp modulation on digestion of nutrients. Rifampicin treatment upregulated duodenal P-gp in dogs and significantly reduced the area under the plasma concentration-time curve of prednisolone. Ketoconazole typically downregulated expression of duodenal P-gp, with a subsequent increase in the area under the plasma concentration-time curve of prednisolone. There was a noticeable interindividual difference in response. Digestion of nutrients was not affected. Modulation of P-gp expression influenced plasma concentrations of prednisolone after oral administration in dogs. Thus, treatment response to prednisolone may be influenced by coadministration of P-gp-modulating medications or feed ingredients.

Effect of plasma lipid on pharmacokinetics of ciclosporin and its relationship with plasma prednisolone level in renal transplant patients

Ciclosporin (cyclosporine A, CyA) is a potent immunosuppressant used after organ transplantation. The pharmacokinetic properties of CyA vary widely and lipoproteins are the major complexing constituents for CyA in the plasma. Therefore, a change in lipoprotein level may influence the pharmacokinetic properties of CyA. Prednisolone (PSL) is concomitantly used with CyA as an immunosuppressant. After organ transplantation, hyperlipidaemia resulting from PSL therapy has been mostly observed and PSL increased the plasma lipoprotein level. Therefore, in this study, to obtain more useful information of the therapeutic drug monitoring (TDM) of CyA, the relationship between the plasma PSL level, plasma lipoprotein level and blood CyA level was investigated in detail. An open-label, non-randomized, retrospective study was performed. Data from 21 male and 11 female patients (age 11-65 years) who received a living-related renal transplantation from 2002 to 2004 were included. On postoperative days (PODs) 7, 14 and 28, the area under the plasma concentration-time curve until 9 h after 40 mg of PSL administration (AUCPSL40(0-9)) correlated well with total cholesterol (T-cho) (r=0.558, 0.768, 0.660, all P<0.05) and high-density lipoprotein (HDL) (r=0.688, P<0.05; 0.835, P<0.01; 0.508, p<0.05), and correlated negatively with very-low-density lipoprotein (VLDL) (r=-0.486, p<0.01; -0.776, p<0.01; -0.967, p<0.01). In addition, AUC until 9 h after CyA administration (AUCCyA0-9) also correlated with T-cho (r=0.797, p<0.01; 0.577, p<0.05; 0.901, p<0.01), HDL (r=0.514, p<0.05; 0.614, p<0.05; 0.893, p<0.01) and low-density lipoprotein (LDL) (r=0.906, p<0.01; 0.573, p<0.05; 0.537, p<0.05), and there was a negative correlation with VLDL (r=-0.480, -0.630, -0.632, all p<0.05). Moreover, AUCCyA0-9 correlated well with AUCPSL40(0-9) (r=0.728, p<0.01; 0.482, p<0.05; 0.688, p<0.05); namely, it was considered that the variety of plasma PSL concentrations influenced the pharmacokinetic properties of CyA through the change in lipoprotein levels. These results suggested that monitoring of the biochemical parameters of the plasma lipid and plasma PSL level might be useful for the TDM of CyA.

Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients

The objective of this study was to evaluate whether genetic polymorphisms of CYP3A5 (A6986G, CYP3A5*3), ABCB1 (C1236T, G2677T/A, C3435T) and NR1I2 (A7635G) significantly impact the pharmacokinetics of prednisolone in renal transplant recipients. Ninety-five recipients were given repeated doses of triple therapy immunosuppression consisting of prednisolone, tacrolimus and mycophenolate mofetil. Twenty-eight days after renal transplantation, plasma prednisolone concentrations were measured by high-performance liquid chromatography. Comparisons of the CYP3A5 and ABCB1 genotypes revealed no significant differences in the prednisolone pharmacokinetics. The mean prednisolone C max for recipients ( n = 14) having both the ABCB1 3435CC genotype and the CYP3A5*3/*3 genotype was significantly higher than those ( n = 11) having both ABCB1 3435TT and CYP3A5*3/*3 genotypes (180 ng/mL versus 129 ng/mL, P = 0.0392). The plasma concentrations of prednisolone in recipients having both ABCB1 3435CC and CYP3A5*3/*3 genotypes tended to be higher than those having both ABCB1 3435TT and CYP3A5*3/*3 genotypes. The mean AUC 0–24 and C max values for prednisolone in recipients having the NR1I2 7635G allele (AG: n = 45, GG: n = 32) were significantly lower than in patients having the 7635AA allele ( n = 18) (7635GG versus 7635AA, P = 0.0308 for AUC 0–24, P = 0.0382 for C max of prednisolone). In conclusion, NR1I2 (A7635G) rather than CYP3A5 or ABCB1 allelic variants affected patient variability of plasma prednisolone concentration. Recipients carrying the NR1I2 7635G allele seemed to possess higher metabolic activity for prednisolone in the intestine, greatly reducing its maximal plasma concentration.

Simultaneous determination of prednisolone, prednisone, cortisol, and cortisone in plasma by GC–MS: Estimating unbound prednisolone concentration in patients with nephrotic syndrome during oral prednisolone therapy

Individual variability of the pharmacokinetics of prednisolone based on the unbound concentration in plasma is of significant clinical consideration. The unbound concentrations of prednisolone were measured in 10 patients with nephrotic syndrome, two patients with systemic lupus erythematosus, and one patient with dermatomyositis by examining protein bindings of prednisolone on one or more occasions during prednisolone treatment. In this study, plasma concentrations of prednisolone, prednisone, cortisol, and cortisone were simultaneously analyzed by GC–MS by using stable isotope-labeled internal standards. Equilibrium dialysis was employed to accurately estimate the unbound fractions of prednisolone in plasma. The unbound fraction of prednisolone changed depending on plasma total prednisolone concentration and plasma albumin concentration. The unbound fraction of prednisolone ( Y) is calculated: Y = (−0.0101 x′ + 0.0736) x + 10.23, where x′ is the plasma albumin concentration and x is the total prednisolone concentration. The estimated concentrations of unbound prednisolone by using the above equation were in good agreement with the measured concentrations of unbound prednisolone. Since the protein binding of prednisolone did not change in the presence of prednisone (114.0 ng/ml), it appeared that prednisone produced from the therapeutic dose of prednisolone did not affect the unbound fraction of prednisolone.

Study on the Colon Specific Delivery of Prednisolone Using Chitosan Capsules

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Gastrointestinal distribution and absorption behavior of Eudragit-coated chitosan–prednisolone conjugate microspheres in rats with TNBS-induced colitis

Conjugate of chitosan and succinyl-prednisolone, termed Ch–SP, was synthesized, and Ch–SP microspheres (Ch–SP-MS) and Eudragit L100-coated Ch–SP-MS (Ch–SP-MS/EuL) were prepared using Ch–SP. Ch–SP-MS and Ch–SP-MS/EuL had a mean size of 1.5 and 26.6 μm, respectively, and a drug content of 4.6 and 3% (w/w), respectively. Prednisolone (PD) was released very slow in JP 14 first fluid (pH 1.2), and gradually in JP 14 second fluid (pH 6.8). The addition of cecal or colonic content did not accelerate the release. Rats with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were used in animal studies. Gastrointestinal distribution and plasma concentration were investigated by oral administration of PD alone and Ch–SP-MS/EuL. For PD alone, PD was distributed at the stomach and small intestine, and disappeared from the gastrointestinal tracts within 8 h. When administering Ch–SP-MS/EuL, the drug was distributed mainly in the lower intestine between 3 and 24 h. Plasma concentration was much lower in Ch–SP-MS/EuL than in PD alone, suggesting lower toxic side effects of Ch–SP-MS/EuL. Thus, Ch–SP-MS/EuL delivered PD specifically near the diseased site and PD was released gradually, with much less plasma concentration of PD. Ch–SP-MS/EuL are suggested as a useful delivery system to the site of inflammatory bowel disease.

Study on the Colon Specific Delivery of Prednisolone Using Chitosan Capsules

In this study, we examined the effectiveness of chitosan capsules for the colon-specific delivery of prednisolone in rats. We also evaluated the effectiveness and side effects of prednisolone using chitosan capsules compared with the conventional dosage form (gelatin capsules). We found a significant increase in the concentration of prednisolone in the large intestinal mucosa when prednisolone was administered orally using chitosan capsules, as compared with the case using gelatin capsules. On the other hand, the plasma concentrations of prednisolone after oral administration using chitosan capsules were much lower than those in the case of gelatin capsules. We also assessed the effectiveness of prednisolone for the healing of trinitrobenzene sulfonic acid-induced colitis by measuring myeloperoxidase (MPO) activity and colon wet weight/body weight (C/B) ratio. MPO activities and C/B ratios were significantly reduced when prednisolone was administered orally using chitosan capsules, in comparison with the case of gelatin capsules. Moreover, the weight of the thymus, which is an index of the side effects of prednisolone, markedly decreased after oral administration of prednisolone using gelatin capsules, whereas its weight did not change as much when prednisolone was administered orally using chitosan capsules. These findings indicate that chitosan capsules might be useful for the colon-specific delivery of prednisolone and its enhanced effectiveness for the healing of colitis in rats. Moreover, chitosan capsules might be also effective in reducing the side effects of prednisolone due to its decreased intestinal transfer to the systemic circulation.

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.