Clinical Pharmacokinetics of Prednisone and Prednisolone

Abstract

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 I 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 thefrequently 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.

Biowaiver Monographs for Immediate Release Solid OralDosage Forms: Prednisolone

“…The systemic availability is almost complete and reported to range from 75% to 98%, [11], [14], [30][31][32][33][34][35][36][37][38][39] with a concentration-time profile that is very similar to that when prednisone is taken orally. [40], [41] Maximum serum concentrations occur within 1-2 h after administration of a single dose.…”

“…[40], [41] Maximum serum concentrations occur within 1-2 h after administration of a single dose. [10], [11], [14], [31], [32], [35], [42][43][44] Food intake prolongs the time to peak concentration, but does not affect the extent of absorption. [45][46][47] No indication of existence of an absorption window was found in the literature.…”

“…[44] The concentration-dependent binding of prednisolone to the plasma proteins (i.e., transcortin and albumin) results in the dose-dependent nonlinear pharmacokinetics observed for prednisolone. [11], [50], [51] Transcortin has high affinity and low capacity binding sites while albumin has low affinity and a high capacity for binding prednisolone. The fraction bound is not constant and decreases in a nonlinear fashion with increasing concentrations: at low concentrations protein binding appears to be quite high (80%-90%), but declines at higher prednisolone levels to 60%-70%.…”

“…[51] Distribution and elimination of prednisolone have been described in terms of a twocompartment open model, with rapid distribution within the first half-hour followed by a slower terminal elimination phase. [11], [36] Prednisolone is able to penetrate the blood-brain barrier, reaching about 1/10 of the serum concentration in cerebrospinal fluid. Like all glucocorticosteroids, prednisolone crosses the placenta.…”

“…Both steroids undergo a reversible and dose-dependent metabolism. The interconversion equilibrium strongly favors the formation of prednisolone, [11], [40] resulting in a ratio of prednisolone to prednisone plasma concentrations of 4:1 to 10:1. [44], [58] The nonlinear interconversion varies with time and dose.…”