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Atopic dermatitis of sensitive areas such as the face, particularly in children, is a difficult disease to treat as the standard therapeutic, topical steroids, is contraindicated for this application in children. Hydrocortisone (HC) can be used in these instances because it has been shown to be safe, but is often ineffective as it is a relatively weak steroid, especially at over-the-counter concentrations. To enhance the local topical activity of HC, the terminal inactive metabolite of prednisolone, Δ(1)-cortienic acid (Δ(1)-CA), is added to HC, as Δ(1)-CA preferentially binds transcortin, liberating more HC to elicit its therapeutic effect. Skin blanching studies, which are used to evaluate the potency of topical steroids, were employed to assess the ability of Δ(1)-CA to enhance the activity of HC. The results demonstrate that Δ(1)-CA, when applied in combination with HC, does indeed potentiate the vasoconstriction effect of topically applied HC, while having no effect alone. Thus, addition of the inert prednisolone metabolite Δ(1)-CA can increase the therapeutic effect of over-the-counter concentrations of HC when applied topically., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The purpose of this work is to delineate the release mechanisms of a sparingly water-soluble drug, prednisolone (PDL), from a microporous or controlled porosity-osmotic pump pellet (CP-OPP) using sulfobutylether-beta-cyclodextrin (CD) as both a solubilizing and osmotic agent. All factors, osmotic and diffusional, influencing drug release as described by the Theeuwes and Zentner equation were partially demonstrated in an earlier paper1 and are further quantitatively evaluated here to determine whether the equation may be applied to CP-OPPs. The PDL release rate from the CP-OPPs containing precomplexed PDL follows the zero-order kinetics for up to 30-40% of drug release during the first 1-2 h and subsequently nonzero order kinetics. The zero-order drug release phase reveals the main contribution is from osmotic pumping with a negligible diffusion component, resulting from the nearly constant driving forces in the system. The nonzero order drug release phase is associated with the dynamic changes in the system (e.g., declining osmotic driving force and greater diffusion component with time). In addition, the parameters related to membrane characteristics were determined, and the effect of viscosity was evaluated for the pellet system. The membranes coated on the CP-OPPs are less permeable to water or solutes than the membranes coated on the previously reported tablets. The viscosity due to the CD decreases as a function of CD concentration, which partly affects the observed drug release profiles. The viscosity effect of CD is significant and captured in a hydraulic permeability term., ((c) 2008 Wiley-Liss, Inc.)

The pharmacodynamic interactions between recombinant mouse interleukin-10 (IL-10) and prednisolone were examined in lipopolysaccharide (LPS)-induced experimental endotoxemia in Balb/c mice. Treatment phases consists of single doses of IL-10 (10 microg/kg i.p.), prednisolone (25 (mg/kg i.p.), IL-10 (2.5 microg/kg i.p.) with prednisolone (6.25 mg/kg i.p.), or placebo (saline). Measurements included plasma steroid kinetics and IL-10 concentrations and responses to LPS including proinflammatory cytokines (TNF-alpha, IFN-gamma) and circulatory NO measured as plasma nitrate/nitrite concentrations. The intraperitoneal dosing of LPS produced large and transient elevations of plasma TNF-alpha, IFN-gamma, and NO concentrations. Noncompartmental and model fitting using extended indirect response models based on drug inhibition of multiphase stimulation of biomarkers by LPS were used to describe the in vivo pharmacodynamics and drug interactions. Dosing with prednisolone, IL-10, or their combinations produced strong inhibition of cytokine and NO production. The IC50 values of prednisolone ranged from 54 to 171 ng/mL, and IC50 values for IL-10 ranged from 0.06 to 0.69 ng/mL. The production of NO was described as a cascading consequence of the TNF-alpha and IFN-gamma plasma concentrations. The joint dosing of IL-10 with prednisolone produces moderately synergistic immunosuppressive effects in this system. Both drugs were sufficiently protective in suppressing the inflammatory mediators when administered prior to the LPS trigger, while such effects were modest when administered after the inflammatory stimulus was provoked. The integrated and complex pharmacokinetic/pharmacodynamic models well capture the in vivo processes, drug potencies, and interactions of IL-10 and prednisolone., (Copyright 2005 Wiley-Liss, Inc. and the American Pharmacists Association.)

The interaction between steroid hormones and intestinal P-glycoprotein was investigated by measuring intestinal absorption from rat small intestine in situ. Prednisolone and hydrocortisone were rapidly absorbed from the entire small intestine. In contrast, methylprednisolone absorption was significantly retarded in jejunum and ileum by an intestinal efflux system. In the presence of verapamil an quinidine, the retarded absorption of methylprednisolone was completely recovered, suggesting that P-glycoprotein is responsible for the unique features of methylprednisolone absorption. A requisite for the substrate of intestinal P-glycoprotein seemed to be 6 alpha-methyl group in the steroid structure. Substrate specificity of intestinal P-glycoprotein to steroid hormones was shown to be in part different from those in other tissues such as adrenal gland. Little of all three steroid hormones disappeared in the supernatant of mucosal homogenate from rat small intestine, indicating that intestinal metabolism of these steroid hormones was relatively small.

The relative serum prednisone and prednisolone concentrations were determined following the administration of prednisone or prednisolone as 5-mg tablets to male beagle dogs. Serum prednisone concentrations were significantly greater following prednisone administration than they were following prednisolone administration. Serum prednisolone concentrations were significantly greater following treatment with prednisolone than with prednisone. The combined prednisone and prednisolone areas under the serum concentration-time curves were similar for the two treatments.

An animal model was sought that would mimic humans with regard to the dose-dependent pharmacokinetics of prednisolone. Four rabbits were each given 0.5 and 10 mg iv of prednisolone, and timed blood samples were obtained. Plasma prednisolone and prednisone concentrations were assayed by high-performance liquid chromatography, and protein binding was assessed using equilibrium dialysis at 37 degrees. Increases in the systemic clearance, volume of distribution at steady state, mean residence time (in three of four rabbits), and variance of residence time occurred as dose was increased. As in humans, prednisolone was partly converted to prednisone in the rabbit. Transcortin and albumin concentrations and their affinity constants for binding prednisolone were also similar to humans.

The in vitro intestinal ring uptake of prednisolone (11 beta,17,21-trihydroxypregna-1,4-diene-3,20-dione), prednisolone 21-succinate, and prednisolone 21-phosphate was compared in rings prepared from rat jejunum and colon. An HPLC assay was developed to determine whether the drug or intact prodrug was taken up by the tissue. In jejunum and colon, the uptake of prednisolone was limited by its solubility (0.84 mM, 37 degrees C). The freely soluble succinate and phosphate esters were well absorbed in the jejunum. The only species detected in jejunal tissue after incubation with prednisolone 21-phosphate was prednisolone, indicating hydrolysis prior to absorption. This implication was verified by light microscopy. Incubation of tissue from the jejunum with prednisolone 21-succinate resulted in uptake of a mixture of prodrug and parent drug, with the latter form predominating. Prednisolone 21-succinate was also absorbed well in the colon, where the predominant species taken up by the tissue was the intact ester. The half-life of the succinate ester in the tissue was approximately 1 h postincubation, implicating enzyme mediation. Uptake of the phosphate ester by the colon was less than 20% of that observed in the jejunum, with the species absorbed still being primarily the parent alcohol. Light microscopy techniques confirmed that prednisolone 21-phosphate and hydrocortisone 21-phosphate are good substrates for brush border membrane alkaline phosphatase in the jejunum, and that lack of this enzyme in colon tissue was most likely responsible for poor uptake in the colon.

The rates of intestinal absorption of salicyclic acid, sulfapyridine, and prednisolone from solutions containing no alcohol or 0.5% ethanol, n-butanol, or n-hexanol were determined. At the concentrations used, ethanol did not significantly affect drug absorption. Butanol reduced the rate of absorption of sulfapyridine but did not significantly affect the absorption rates of prednisolone or salicylic acid. Hexanol reduced the rates of absorption of sulfapyridine and salicylic acid and increased the rate of absorption of prednisolone. The absorption-altering effects of the alcohols were concentration dependent and rapidly reversible. Histological studies indicated that the structure of the epithelium was not altered by the alcohols. While the absorption rate of water from the drug solutions was increased by the alcohols, their absorption-altering effects could not be attributed solely to increased water flux. In addition, the absorption-altering effects of the alcohols could not be attributed to formation of drug-alcohol complexes nor to alcohol-induced alterations in the extent of binding of the drugs to nondialyzable materials in the intestinal drug solution.

The intestinal absorption of hydrocortisone and prednisolone are compared with three water-soluble derivatives (succinate, phosphate, and lysinate) in experiments at two levels of biological system complexity. Rates of absorption are compared by measuring permeabilities from rat intestinal perfusions of drugs and derivatives in solution. Extents of absorption are compared over a 10-fold dose range of parent steroid and with the steroid derivatives by measuring plasma levels from solid oral dosage in dogs. While the parent steroids are well absorbed over the entire length of the intestinal tract, variability in plasma levels is observed at higher doses. Limited solubility and resultant dissolution rate variability are likely to be playing a role in the early erratic blood level profiles found at higher doses. While the soluble prodrugs have a dissolution rate advantage which results in a greater concentration gradient, their absorption is limited by their aqueous luminal stability, their polarity and resultant passive membrane permeability, and the distribution and activity of enzyme reconversion sites in the intestinal tract. The unstable lysinate ester, targeted for aminopeptidase, has an absorption profile and permeability similar to that of the parent steroid. The absorption of the moderately stable succinate ester is limited by its polarity and the activity of intestinal esterases. The stable phosphate derivative is well absorbed in the upper intestine, where high levels of alkaline phosphatase exist, while the prodrug polarity and drop-off of enzyme activity limit its absorption from the lower gastrointestinal (GI) tract.

The absorption rates of griseofulvin and prednisolone were measured from solutions that were recirculated through a segment of in situ rat jejunum. When premicellar concentrations of butyric, octanoic, or dodecanoic acid were present in the perfusate, the griseofulvin absorption rate decreased while that of prednisolone increased. The fatty acids also increased the absorption rate of water from the perfusate, and the effect of butyric acid was attributed primarily to this increase. The absorption-altering effects of octanoic and dodecanoic acids could not be attributed solely to their effects on water absorption nor to their effects on the surface tension of the perfusate. The effects of octanoic and dodecanoic acids were explained by postulating different rate-limiting barriers to the absorption of prednisolone and griseofulvin.

With a fasted dog as an animal model, the bioavailability and pharmacokinetics of prednisolone were studied following rapid intravenous injection and oral dosing of a prednisolone sodium phosphate solution and also following oral doses of prednisolone as tablets and a slurry. Hydrolysis of the phosphate ester to prednisolone in the body is extremely rapid and complete, thus permitting accurate calculation of the distribution volume of prednisolone. Enteral absorption of prednisolone from a slurry is superior to that from prednisolone tablets and from a prednisolone sodium phosphate solution. Reduced absorption from tablets, compared to the slurry, is probably due to tablet disintegration characteristics; reduced absorption from the solution is probably due to poor membrane permeability of the ionized drug. Information obtained from a single animal may indicate the need for expanded studies in humans.

Binding of prednisolone to rabbit tissue was determined experimentally and by computation to assess factors and proteins responsible for tissue distribution of this corticosteroid. Binding in tissue slices ranged from 36% in the lung to 83% in the liver. The results obtained were compared with steady-state tissue distribution data generated in vivo in the rabbit. Linear uptake with good agreement between the two sets of data was observed for the skeletal muscle and kidney, but not for the liver and lung. In vivo uptake of prednisolone in the liver is severely affected by metabolism and biliary excretion, while in vitro distribution into liver slices showed a pattern typical of saturation of a low-capacity site followed by linear nonspecific binding at higher concentrations. Specific saturable binding (K1 = 1.95 X 10(7) M-1) accounted for 74% of drug bound at a steroid concentration in the liver of 0.3 X 10(-6) M, but its contribution decreased to 5% at a concentration of 20 X 10(-6) M. Expected prednisolone binding in rabbit tissue was calculated based on various effective protein concentrations in tissues and binding parameters of prednisolone to rabbit plasma. The use of total Lowry protein concentrations markedly overestimates, while albumin (and transcortin) concentrations severely underestimate the tissue binding of prednisolone. The thiopental effective protein fraction best approximates the in vivo and tissue slice binding of prednisolone. Metabolism and saturable binding in liver complicate the otherwise relatively linear uptake of prednisolone into various tissues where macromolecules other than albumin dominate in tissue binding of the steroid.