Pharmacokinetics Of Prednisolone Research Articles

Dose-Dependent Protein Binding and Disposition of Prednisolone in Rabbits

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°. 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.

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.

Prednisolone disposition in cushingoid and noncushingoid kidney transplant patients.

Little information is available on the disposition of prednisolone in kidney transplant patients and whether correlations exist between the pharmacokinetics and therapeutic or toxic effects of this drug. The present study was designed to determine the pharmacokinetics of prednisolone in six noncushingoid and six cushingoid transplant recipients. The elimination half-lives were not significantly different in the noncushingoid and cushingoid patients (2.3 vs. 3.3 h). However, other pharmacokinetic parameters were significantly lower in the cushingoid group: plasma clearance (147 vs. 82 ml/min) and volume of distribution (32 vs. 20 liters). In addition, the availability of prednisolone after oral prednisone administration was considerably variable (overall range, 27-108%) and was not significantly different between the two groups. Thus, in kidney transplant patients it appears that the plasma clearance and volume of distribution of prednisolone may distinguish between noncushingoid and cushingoid patients.

Prednisolone pharmacokinetics in asthmatic patients

Prednisolone serum levels have been measured by radio-immunoassay in 12 steroid-dependent asthmatic patients. Differences in prednisolone pharmacokinetics did not account for the variation in dose of prednisolone required to control asthma.

Proceedings of the Australian Society for Medical Research.

Proceedings of the Australian Society for Medical Research.

Clinical Pharmacokinetics of Prednisone and Prednisolone

Prednisone and prednisolone are used in a wide variety of diseases. The two compounds are metabolically interconvertible; prednisolone is assumed to be the pharmacologically active species. Prednisone and prednisolone plasma concentrations are commonly determined by either radioimmunoassay or competitive protein binding techniques. No relationship has been demonstrated between prednisolone plasma concentration (unbound or total concentration) and clinical response; alternate day dosage regimens with fluctuating plasma concentrations being considered generally to be as effective with less side effects than a daily dosage regimen. Both drugs are rapidly absorbed after oral administration, reaching peak plasma concentrations after 1 to 3 hours. In general, plasma half-lives for prednisone are slightly longer (3.4 to 3.8h) than for prednisolone (2.1 to 3.5h). Either drug can be prescribed in most situations. On average, however, the bioavailability of prednisolone after oral prednisone is approximately 80% of that after prednisolone. A wide intersubject variation in prednisolone concentration is evident after both drugs, which may suggest impaired drug absorption in some individuals. Prednisolone shows dose dependent pharmacokinetics; an increase in dose leading to an increase in volume of distribution and plasma clearance. This can be explained in terms of the non-linear binding of the drug to plasma proteins. The degree of binding will determine the distribution and clearance of free (i.e. pharmacologically active) drug. Reduced doses are recommended in patients with hypoalbuminaemia. Prednisolone pharmacokinetics are also dependent on age; the half-life being shorter in children. Liver disease prolongs the prednisolone half-life and, due to the frequently associated hypoalbuminaemia, also increases the percentage of unbound drug. It has been recommended by some that prednisolone rather than prednisone is the drug of choice in active liver disease owing to the poor conversion of prednisone to prednisolone in some patients. However, the reduced plasma concentration of prednisolone in such patients is compensated for by delayed clearance. Thus, there is little advantage of one preparation over the other. Pharmacokinetic drug interactions have been reported, particularly accelerated clearance of prednisolone due to enzyme inducing agents such as barbiturates, phenytoin, rifampicin and other corticosteroids. On the other hand, oral contraceptives have been reported to increase the half-life and to decrease distribution volume and clearance of prednisolone, due to the increased levels of corticosteroid binding globulin (transcortin).

Oral prednisone for chronic active liver disease: dose responses and bioavailability studies.

Serum concentrations of prednisolone were measured by radioimmunoassay after the administration of prednisone (10, 20, or 30 mg) by mouth to five healthy volunteers, five patients with severe chronic active liver disease (CALD), and five patients with CALD in remission induced by prednisone. Only minor differences were found between the groups and bioavailability was linearly related to the dose of prednisone (r = 0.993). After prednisone (10 mg) was given by mouth and by vein to similar groups of volunteers and 11 additional patients with CALD, bioavailability of oral prednisone approximated 100% of the intravenous dose and no differences were found in the pharmacokinetics of prednisolone. We conclude that prednisone is effectively absorbed and converted to prednisolone in health and CALD and find no pharmacological evidence that either drug would be superior to the other for treating CALD.

Prednisolone Bioavailability in the Dog

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.