Clinical Pharmacokinetics of Prednisone and Prednisolone

Abstract

The growth of knowledge in the field of the pharmacokinetics of prednisolone/prednisone has been slow for several reasons. First, convenient and specific methods for measuring these steroids only became available with the development of high performance liquid chromatographic methods. Secondly, prednisolone is nonlinearly bound to transcortin and albumin: since the unbound concentrations of prednisolone are biologically relevant, it was necessary to determine the free fraction in each plasma sample. Thirdly, due to the short half-life of prednisolone no steady-state is achieved, and therefore area under the concentration-time curve needed to be determined in all studies. Fourthly, prednisolone and prednisone are interconvertible and prednisolone is given intravenously as an ester prodrug, features which created controversies about the correct interpretation of pharmacokinetic results. Finally, the total body clearances of total and (to a lesser degree) of unbound prednisolone increase with increasing concentrations of prednisolone. Therefore, in order to compare pharmacokinetic results between different subjects, standardised doses had to be administered. The investigations performed so far have revealed that: (1) the dose-dependent pharmacokinetics partly explain the clinical observation that an alternate-day regimen with prednisone yields fewer biological effects; (2) the interconversion of prednisone into prednisolone is not a limiting factor, even in patients with severely impaired liver function; (3) hypoproteinaemia per se does not cause increased unbound concentrations of prednisolone in vivo; (4) patients with liver failure, renal failure or a renal transplant, subjects older than 65 years, women on estrogen-containing oral contraceptive steroids or subjects taking ketoconazole have increased unbound concentrations of prednisolone-whereas hyperthyroid patients, some patients with Crohn's disease, subjects taking microsomal liver enzyme-inducing agents or patients on intravenous prednisolone phthalate (instead of prednisolone phosphate) or on some brands of enteric coated prednisolone tablets have decreased concentrations of prednisolone. The biological relevance of the altered pharmacokinetics is supported in part by altered clinical effects and altered effects on cellular immunofunctions.

Enfermedad inflamatoria intestinal en pacientes mayores de 60 años: ¿es una enfermedad diferente?

“…En consecuencia, en nuestra opinión las estrategias farmacológicas no deben ser modificadas como resultado de la edad del paciente, destacando que la subutilización de estos fármacos puede estar asociada a un mal control de la enfermedad en la población geriátrica 32 . Pese a esto, se debe tener presente los cambios fisiológicos en la biodisponibilidad de los esteroides 33 , ya que ellos pueden aumentar los eventos adversos en este grupo etario 34 . Junto con ello, es necesario considerar que la edad ha sido señalada como un factor de riesgo de linfoma y cáncer de piel no-melanoma en pacientes expuestos a fármacos inmunosupresores [35][36][37] , y de severas infecciones en pacientes que se encuentran con terapia inmunosupresora y biológica 37,38 .…”

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

“…Protein binding of prednisolone decreases nonlinearly from 95% to 60-70%, while the concentration increases from 200 60-70%, while the concentration increases from 200 μg/L to 800 μg/L when protein binding of prednisolone reaches the stationary state (Rose et al, 1981). In consequence, a dosedependent increase in the volume of distribution (Vd) and drug clearance (CL) is observed at doses over 20mg (Frey et al, 1990;Rohatagi et al, 1997). However, the elimination halflife remains constant and the dose dependencies of Vd and CL disappear when free prednisolone concentrations are measured (Möllmann et al, 1989;Rohatagi 1997).…”

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.…”

“…The total body clearance of prednisolone has been reported to be 111 mL/min/1.73 m2 for a 5 mg dose and 194 mL/min/1.73 m2 for a 40 mg dose of prednisolone. [35], [44] Renal elimination comprises 40% of total elimination. [65] The mean elimination half-life increases with the dose and ranges from 2.1 to 3.5 h. [11], [33], [66] The half-life in children is shorter than that recorded in most adult studies.…”