Background: Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase.Methods: This single-center, prospective, observational study included stable renal Tx recipients, .18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC 0-24 )], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography2tandem mass spectrometry. Results:In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC 0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = 20.83) between PL AUC 0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC 0-24 was PL C 6 (r 2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC 0-24 with a low percentage prediction error (PPE = 5.2 6 1.5%) and a good correlation of determination (r 2 = 0.91). PL AUC 0-24 varied 3-fold among study participants, whereas CL AUC 0-24 varied by 18-fold. Conclusions:The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC 0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.

Because several steroid hormones are metabolized to their respective 6β-hydroxy forms by CYP3A4 and CYP3A5, these isoenzymes have been assumed to metabolize the immunosuppressive drug prednisolone, with conflicting results in the literature with respect to their relative importance. A direct study of the metabolism of prednisolone by microsomal CYP3A4 and CYP3A5 is missing. The aim of this in vitro study was to investigate the relative importance of recombinant CYP3A4 and recombinant CYP3A5 in the metabolism of prednisolone and to compare the extent of formation of 6β-OH-prednisolone by the two enzymes. Through in vitro incubations using rCYP3A4 and rCYP3A5 enzymes, intrinsic clearance (CL int ) of prednisolone was determined by the substrate depletion approach. Formation of the metabolite 6β-OH-prednisolone by rCYP3A4 and rCYP3A5, respectively, was compared. Prednisolone concentrations were measured, and its metabolite 6β-OH-prednisolone was identified using a HPLC-MS/ MS in-house method. CL int for prednisolone by rCYP3A5 was less than 26% relative to rCYP3A4. Formation of 6β-OH-prednisolone by rCYP3A5 was less than 11% relative to rCYP3A4. The study indicates that 6β-hydroxylation of prednisolone assessed in vitro in recombinant CYP enzymes depends on rCYP3A4 rather than rCYP3A5 and that CYP3A5 may be responsible for the formation of other prednisolone metabolite(s) in addition to 6β-OH-prednisolone. | INTRODUCTION AND BACKGROUNDPrednisolone is a synthetic glucocorticoid administered in a wide range of conditions that require antiinflammatory or immunosuppressive treatment, such as autoimmune diseases and malignancies, and after organ transplantation. Glucocorticoid therapy is, however, associated with a considerable variability in both desired and unwanted effects, and even at relatively low comparable bodyweight (BW)-adjusted doses, a wide range of unwanted side effects including hyperglycaemia,

The study suggests that a high prednisolone/prednisone AUC ratio may be a possible risk factor for NODAT. Further studies of individualization of glucocorticoid treatment in pediatric organ Tx are warranted.