Search

Purpose: To investigate pharmacokinetic differences between the nonhalogenated double ester prednicarbate (PC) and the fluorinated monoester betamethasone 17-valerate (BM17V) their metabolism in human keratinocytes and fibroblasts as well as their permeation and biotransformation in reconstructed epidermis and excised human skin was compared. Special attention was given to the 17-monoesters because of their high receptor affinity and antiproliferative effects., Methods: Glucocorticoid penetration was determined using Franz diffusion cells, quantifying metabolite concentrations by HPLC. Chemical stability and reactivity of the monoesters was determined by molecular modeling analysis., Results: PC accumulated in the stratum corneum. A considerable amount of penetrating PC was hydrolyzed by viable keratinocytes to prednisolone 17-ethylcarbonate (PI7EC), P17EC permeated the skin very rapidly when compared to BM17V. Overall P17EC concentrations in viable tissue were low. Inside of the acceptor fluid, but not within the tissue, P17EC was converted to the more stable prednisolone 21-ethylcarbonate (P21EC)., Conclusions: The inactivation of highly potent, but also cell toxic, 17-monoesters to almost inactive 21-congeners seen with isolated cell monolayers appears less important in the skin. In vitro determination of the dermal 17-monoesters concentrations may allow the prediction of the atrophogenic risk in man. BM17V levels exceeding P17EC concentration about 6-fold may contribute to its lower tolerance when compared to PC.

Purpose: The effect of ultrasound on skin penetration and metabolism of prednisolone (PN) and prednisolone 21-acetate (PNA) was investigated in the hairless mouse skin in vitro., Methods: The abdominal skin excised freshly was pretreated under different ultrasound intensities (4.32, 2.88, and 1.50 W/cm2) for 10, 30, and 60 min. The penetration/metabolism rate of PNA and its metabolite (PN) was then measured using a side-by-side diffusion cell., Results: The skin penetration of PN was enhanced by the ultrasound pretreatment. This enhancement was attributed to the decrease in the stratum corneum barrier capacity by ultrasound energy. The steady-state appearance rate of PN following the skin bioconversion of PNA decreased appreciably with increasing the product of the duration of pretreatment (Dp, min) and the intensity of ultrasound applied (Iu, W/cm2). When the product value was less than 40 W/cm2 . min, the steady-state appearance rate of the PN hardly increased in spite of the penetration enhancement of PNA., Conclusions: These findings indicated a possible deactivation of the skin enzymes by ultrasound energy.

Purpose: Evaluation of skin layer-specific prednicarbate (PC) biotransformation, possibly explaining the improved benefit/risk ratio of this topical corticosteroid in atopic dermatitis (1,2)., Methods: Metabolism of PC in keratinocyte and fibroblast monolayers derived from human juvenile foreskin was evaluated. Drug concentration was determined by HPLC/UV-absorption. Accompanying cell viability tests (MTT-tests) were performed to exclude toxic drug effects., Results: Keratinocytes hydrolyzed the double ester PC (2.5 x 10(-5) M) at position 21 to the monoester prednisolone 17-ethylcarbonate (P17EC) which nonenzymatically transformed to prednisolone 21-ethylcarbonate (P21EC). This metabolite was enzymatically cleaved to prednisolone (PD), the main biotransformation product at 24 hours. Fibroblasts, however, showed a distinctively lower enzyme activity. Both, PC and P17EC (or rather P21EC) were hydrolyzed to a minor extent only. The biotransformation pathway, however, was the same. When P17EC was added separately, it transformed to P21EC and again was cleaved by keratinocytes to a much higher extent. Despite of the rather high glucocorticoid concentration MTT-tests proved a non-disturbed cell viability and proliferation rate., Conclusions: Extrapolating our results to the in-vivo situation, topically applied PC may be metabolized by epidermal cells during skin penetration. A complex mixture of compounds reaches the dermis, whose fibroblasts are barely able to metabolize the steroids. Since skin atrophy is less pronounced with PC as compared to conventional halogenated glucocorticoids, less potent PC metabolites appear to be the dominant species in the dermis.

Purpose: Skin binding of prednisolone and its esters was investigated in the hairless mouse skin in vitro., Methods: The distribution of the amount of drugs bound in the skin was determined by a skin slicing technique. The model drugs used were prednisolone (PN, M.W. 360) and its esters, senesyonate (PN-C5, M.W. 442), geranate (PN-C10, M.W. 510), farnesylate (PN-C15, M.W. 578), and geranylgeranate (PN-C20, M.W. 646)., Results: The distribution of bound drug was nonhomogeneous in the skin; the concentration of PN-C10 and PN-C15 in the skin increased gradually with the distance from the skin surface. The parent drug, PN, however, was hardly bound in the viable skin., Conclusions: These findings suggest that the prodrugs of prednisolone may prolong the dermal retention of the parent drug and minimize to delivery into the systemic circulation of the prodrug and metabolite.

The diffusion and metabolism of prednisolone 21-farnesylate were investigated in viable skin of the hairless mouse in vitro. The prodrug ester was extensively metabolized in viable skin, while it was stable in the donor and receptor solutions. The rate of appearance of the prodrug and its metabolite prednisolone was markedly influenced by the direction of the skin placed between the in vitro diffusion half-cells. The rate of bioconversion of the prodrug was determined as a function of the distance from the surface of the skin. The prodrug was increasingly metabolized with the distance from the surface of the skin, indicating that the responsible enzymes are enriched in the lower layers of the viable skin. A model with linearly increasing enzyme activity in the viable skin accounts for the in vitro profiles of the diffusion/metabolism of the prodrug in the viable skin of hairless mouse.

In a release study of alginate gel beads, swelling and erosion of the beads were observed at pH 6.8, whereas no swelling occurred at pH 1.2. The amount of released prednisolone (PL) was greater at pH 6.8 than at pH 1.2. The lower the ratio of mannuronic acid block to guluronic acid block in alginate, the slower the release of PL. An increase in loaded PL in the beads resulted in a slower release of PL. The decrease in bead size caused a rapid release of PL. The addition of sodium alginate propylene glycol ester elevated the extent of PL release. The plasma profile of PL showed sustained-release behavior after the oral administration of the beads to beagles. Furthermore, the correlation between in vitro release and in vivo absorption of PL for various alginate gel beads was evaluated using deconvolution and convolution methods. The in vivo absorption of PL was correlated with the PL release at pH 1.2, and it differed from that at pH 6.8. The release of PL from alginate gel beads in vivo appeared to occur under conditions that cause little swelling.

Several approaches to receptor down-regulation were examined to extend previous receptor/gene-mediated pharmacokinetic/dynamic models of corticosteroids. Down-regulation of the glucocorticoid receptor was considered as an instantaneous event or as a gradual steroid-receptor-mediated process. Concentrations of plasma methylprednisolone, free hepatic cytosolic receptors, and the activity of hepatic tyrosine aminotransferase (TAT) enzyme were measured for 16 hr following administration of 0, 10, and 50 mg/kg methylprednisolone sodium succinate to 93 adrenalectomized rats. Receptor down-regulation was best described by a fractional decrement in the rate of return of free cytosolic glucocorticoid receptor. Predicted values for free receptor, bound receptor, nuclear bound receptor, and transfer compartments were in accord with the expected rank order values based on the high and low steroid doses. Model parameter estimates were independent of dose and described the rapid depletion of free cytosolic receptor, late-phase return of cytosolic receptor to a new baseline level that was 20-40% lower than control, and the TAT induction/dissipation pattern following steroid dosing. The microscopic association and dissociation constants describing the steroid-receptor interaction were 0.23 L/nmole per hr (k(on)) and 4.74 hr-1 (k(off)) for methylprednisolone compared to previously obtained values of 0.20 L/nmole per hr and 15.7 hr-1 for the related steroid prednisolone. The time course of TAT induction was similar to that observed previously for prednisolone. Efficiency of TAT induction was more closely related to steroid receptor occupancy than plasma methylprednisolone concentrations due to receptor saturability and receptor recycling.

The pharmacokinetics of prednisolone and prednisone were examined in 32 rats at four intravenous doses (5, 10, 25, and 50 mg/kg). Each rat was given one dose of either intravenous prednisolone or prednisone, and plasma concentrations of both compounds were measured by HPLC. Mammillary moment analysis showed the apparent clearance and volume of distribution of prednisolone and the apparent clearance of prednisone to be dose-dependent. Further diagnostic analysis using a linear interconversion model revealed modest interconversion between the two steroids and at least two saturable clearance processes: the conversion of prednisolone to prednisone and the irreversible elimination of prednisone. A comprehensive model which incorporates the nonlinear clearances of prednisolone and prednisone plus the additional feature of nonlinear tissue distribution of prednisolone was then constructed. Four differential equations describing the rate of change of each steroid in each compartment were used to numerically fit by nonlinear least squares analysis all plasma concentration-time profiles simultaneously. The final estimates from the full model only partly agreed with the results from the two moment analyses but confirmed the general structure of the model. The nonlinear tissue distribution of prednisolone was reinforced by assay of muscle tissue. This study demonstrates the utility of the model-building process where simpler models yield insights into more elaborate schemes with complex nonlinear features.

Our receptor/gene-mediated model of corticosteroid action was tested and extended by examining the pharmacokinetics/dynamics of multiple low doses vs. a single higher dose of intravenously administered prednisolone in adrenalectomized male Wistar rats. Low-dose rats received 3 bolus doses (5 mg/kg) of prednisolone at 0, 0.5 and 1.0 hr. High-dose animals were given a single 25 mg/kg dose of prednisolone. Both regimens were expected to produce equivalent net responses based on model predictions. Control rats were not dosed. The profiles of free hepatic cytosolic glucocorticoid receptors and the hepatic tyrosine aminotransferase (TAT) enzyme were examined. Plasma prednisolone concentrations showed bi-exponential decline for both doses using pooled animal data. Clearance of total plasma prednisolone was 4.16 and 3.21 L/hr per kg in low- and high-dose groups. Volume of distribution at steady state (approximately 1.50 L/kg) and central volume (approximately 0.6 L/kg) were similar for both groups. Receptor levels from 5-16 hr stabilized at 64% of the 0-hr control value. Receptor and TAT profiles were essentially superimposable for both dosing groups. Our previous model was used to simultaneously describe prednisolone plasma concentrations, hepatic receptors, and TAT activity. The ability of total plasma prednisolone (Cp), corticosteroid binding globulin (CBG)-free plasma prednisolone (CCBG), and free plasma prednisolone (CF) to describe the kinetics/dynamics were examined. The CF values produced optimum fitting of all receptor data. The similarity of the two dosing groups supports the view that appropriately timed doses of a steroid can be used in an optimally efficacious manner by first filling all receptor sites and then replacing steroid as receptors are expected to recycle from nuclear/DNA binding sites as the steroid is eliminated.

The binding and solubility of nitrofurantoin, piroxicam, indomethacin, prednisolone, diazepam, dicumarol, and griseofulvin in milk were determined at 15, 25, and 37 degrees C in bovine milk samples with fat contents of 0.75 and 3.50%. Drug binding to milk components was independent of drug concentration over the drug concentration studied, and the fat content of milk strongly affected binding values of most of the listed drugs. Further, drug binding increased with decreasing temperatures for most of the drugs examined. The solubility of all drugs is greatly enhanced in milk compared to their aqueous solubility (pH 6.5 phosphate buffer). The high solubility cannot be accounted for solely on the basis of drug binding to milk components. An attempt is made to correlate the binding and solubility data with physicochemical properties of the drugs (logP, pKa, aqueous solubility). The potential significance of these findings is discussed with regard to preparation and in vivo delivery of drugs from drug-milk formulations.

Limited information is available on the pharmacokinetics and bioavailability of prednisone and prednisolone in patients with different disease states. This is partly due to difficulty in measuring these drugs in biological fluids at the usual dosages prescribed to patients. This article attempts to comprehensively review these studies categorized under the following four sections: (1) bioavailability--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of antacids, effect of food, effect of other drugs (aminophylline, cholestyramine); (2) pharmacokinetics--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of other drugs, enzyme induction of steroids and the effect on the kinetics of steroids and other drugs; (3) protein binding; and (4) analytical methods. The literature is reviewed through August 1979.

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.

A pharmacokinetic/pharmacodynamic model describing receptor-mediated effects of prednisolone is presented. The basis of the model is the generally accepted mechanism of action of steroid hormones in which corticosteroids bind to cytosolic receptors forming steroid-receptor complexes, which are activated and translocated into the nucleus. There the complexes associate with specific DNA sequences and modulate the rate of transcription of DNA into specific RNAs that code for the synthesis of proteins that elicit biological responses. Prednisolone, 5 or 50 mg/kg, was administered intravenously to adrenalectomized rats. Total plasma, free plasma, CBG-free plasma, and liver prednisolone concentrations were measured simultaneously with free hepatic cytosolic glucocorticoid receptor concentrations and tyrosine aminotransferase (TAT) activity of the liver as a function of time. The association/dissociation kinetics of prednisolone binding to the glucocorticoid receptor were measured separately in vitro at 37 degrees C. Total plasma, free plasma, and CBG-free plasma prednisolone concentrations could be used equally well in the model to account for the time course of receptor concentrations and TAT activity. However, use of liver steroid concentrations resulted in an overestimation of receptor depletion. Steroid concentrations in plasma increased 20 to 30-fold with a tenfold increase in dose, but receptor occupancy and TAT activity over time increased about threefold. While prednisolone pharmacokinetics were dose-dependent, parameters describing receptor kinetics and TAT activity were constant at each prednisolone dose. The major determinants of receptor-mediated glucocorticoid activity are confirmed to be the availability of the receptor, drug-receptor dissociation rate, and corticosteroid persistence in the biophase.

The pharmacokinetics of oral prednisone and oral dexamethasone were examined in 18 healthy male adults. Eight subjects also received intravenous prednisolone and intravenous dexamethasone. Half of each group were cigarette smokers as confirmed by plasma thiocyanate concentrations. Plasma and urine concentrations of prednisone and prednisolone were assayed by high performance liquid chromatography, while plasma dexamethasone was measured by radioimmunoassay. There were no statistically significant differences between smokers and nonsmokers in the systemic availability of prednisolone (75 versus 84%), oral dose clearance of prednisone (29 verus 27 ml/min/kg), systemic prednisolone clearance (2.8 versus 2.9 ml/min/kg), or in the interconversion rates, volumes of distribution, or urinary recoveries of prednisone and prednisolone. Similarly, the pharmacokinetics of dexamethasone were unaffected by smoking. A limited correlation (r = 0.55) was found between the high oral dose clearances of prednisone and the lower values of dexamethasone (6.73 and 5.71 ml/min/kg in smokers and nonsmokers). A two- to threefold variability occurred in oral dose clearances of each steroid with partial intrasubject covariance. Unlike the anticonvulsants, which markedly induce corticosteroid metabolism, smoking has no effect on their pharmacokinetics and should not complicate therapy with these drugs.

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.