The Effect of Altered Prednisolone Kinetics in Patients with the Nephrotic Syndrome and in Women Taking Oral Contraceptive Steroids on Human Mixed Lymphocyte Cultures

Abstract

The purpose of this study was to examine the influence of altered prednisolone kinetics in patients with the nephrotic syndrome and women taking oral contraceptive steroids on mixed lymphocyte cultures (MLC). After oral and iv prednisolone treatment, blood samples were collected over 24 h. The area under the plasma concentration vs. time curve (AUC) of unbound, transcortin- bound, and albumin-bound prednisolone was determined. All plasma samples were incubated with MLCs, and the area under the inhibition vs. time curve of the MLC (AUIC), a measure of the effect over time, was calculated. The steroid concentrations required to produce half-maximal inhibition (EC50) were calculated. The 10 women taking oral contraceptives had higher AUCs of unbound and transcortin-bound prednisolone than the 10 normal subjects. The mean biological effect (AUIC value) was more pronounced in women taking contraceptive steroids. An analysis of the concentration-response curves revealed that the EC50 values of total, but not unbound, prednisolone were higher in women taking contraceptives. Compared with the normal subjects, the 9 nephrotic patients had lower total and comparable unbound AUCs of prednisolone. The AUIC values were higher whereas the EC50 values of unbound and total prednisolone were lower in the nephrotic patients. These findings indicate that the increased steroid effect in women taking oral contraceptives is explained by higher concentrations of prednisolone, while the increased effect in nephrotic patients is not attributable to the abnormal kinetics or protein binding of prednisolone.

Risk of Infectious Complications in Patients Taking Glucocorticosteroids

“…In clinical practice one might have to initiate therapy with prednisone in patients who are already suffering from an infection or who are immunocompromised, conditions that might have precluded the participation in a controlled trial with prednisone. Furthermore, certain states, such as renal failure, hepatic disease, old age, or concomitant drug therapy (e.g., ketoconazole or oral contraceptive steroids), decrease the metabolism of prednisolone [95][96][97][98][99][100] and therefore might increase the likelihood of infections even at doses below the threshold doses for increased risk of infections found in the controlled trials. Conversely, Stuck, Minder, and Frey patients with an enhanced catabolism of the steroid because of induced microsomal liver enzymes by xenobiotics (mainly phenytoin, barbiturates, or rifampin) or because of hyperthyroidism exhibit less immunosuppressive effect -and as a corollary less infectious risk -from the same dose of prednisone than do patients with a normal steroid metabolism .…”

Impaired Prednisolone Sensitivities of the Endocrine System and Peripheral-blood Lymphocytes are Closely Related to Clinical Incidence in Renal Transplantation

“…U p until now, no significant relationship had been demonstrated between the plasma concentration of prednisolone and its therapeutic efficacy (Gambertoglio et al 1980). Furthermore, the biological effects cannot be derived directly from the measured concentrations of prednisolone in patients with the nephrotic syndrome for several reasons (Moothy et a1 1976;Rosner et a1 1982;Frey & Frey 1985). Therefore, prednisolone pharmacodynamics, such as those described in this study and those reported by others (Dumbleet a1 1983(Dumbleet a1 , 1986Lowyet a1 1984Lowyet a1 , 1985Langhoff et a1 1986), should be evaluated widely in renal transplant recipients and in patients with chronic renal failure awaiting renal transplantation.…”

Clinical Pharmacokinetics of Prednisone and Prednisolone

“…Madsbad et al for the first time cor· related the pharmacokinetic parameters of pred· nisone with galactose elimination capacity, an independen t quantitauve parameter of liver function. (4) When a 10-foid higher dose of prednisone (1 mg/kg) was given to patients wit h apparently normal li ver fun ction, no saturation of the conversion of prednisone to prc<inisolone was observed (Frey 8M et al 1985), an observation suggesting that In patients with ImpaIred hver function a low dose of pred. and that patie nts exhIbItIng a galactose eliminatIOn capaCity below 284 mg/mm had higher mean concentratIons of prcdmsone than predm.…”