Pharmacokinetics of total and unbound prednisone and prednisolone in stable kidney transplant recipients with diabetes mellitus.
BACKGROUND
The corticosteroid prednisone is an important component of posttransplantation immunosuppressive therapy. Pharmacokinetic parameters of prednisone or its pharmacologically active metabolite, prednisolone, are not well characterized in transplant recipients. The objective of this study was to compare the pharmacokinetics of total and unbound prednisone and prednisolone in diabetic and nondiabetic stable kidney transplant recipients and to evaluate the factors influencing plasma protein binding of prednisolone.


METHODS
Prednisone and prednisolone concentration-time profiles were obtained in 20 diabetic and 18 nondiabetic stable kidney transplant recipients receiving an oral dose of 5-10 mg prednisone per day. In addition to drug and metabolite exposures, factors influencing prednisolone protein binding were evaluated using a nonlinear mixed-effects modeling approach. This model takes into account the binding of prednisolone and cortisol to corticosteroid-binding globulin (CBG) in a saturable fashion and binding of prednisolone to albumin in a nonsaturable fashion. Finally, we have investigated the influence of several covariates including diabetes, glucose concentration, hemoglobin A1c, creatinine clearance, body mass index, gender, age, and time after transplantation on the affinity constant (K) between corticosteroids and their binding proteins.


RESULTS
In patients with diabetes, the values of dose-normalized area under the concentration-time curves were 27% and 23% higher for total and unbound prednisolone, respectively. Moreover, the ratio of total prednisolone to prednisone concentrations (active/inactive forms) was higher in diabetic subjects (P < 0.001). Modeling protein binding results revealed that the affinity constant of corticosteroid-binding globulin-prednisolone (KCBG,PL) was related to the patient's gender and diabetes status.


CONCLUSIONS
Higher prednisolone exposure could potentially lead to the increased risk of corticosteroid-related complications in diabetic kidney transplant recipients.
*Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island; †Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Inc, Groton, Connecticut; and ‡Division of Organ Transplantation, Alpert Medical School of Brown University, Providence, Rhode Island.
Ileana A
IA
Ionita
Ken
K
Ogasawara
Reginald Y
RY
Gohh
Fatemeh
F
Akhlaghi
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D011239:Prednisolone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011241:Prednisone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D066027:Transplant Recipients
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011239:Prednisolone; D011241:Prednisone