Metabolism of Prednisone in Kidney Transplanted Patients with Necrosis of the Femoral Head

Abstract

Interindividual variation of the metabolism of prednisolone and of the susceptibility to glucocorticoids might be possible factors contributing to the development of osteonecrosis after renal allotransplantation. As this aspect has not been properly investigated previously, we compared, in the present study, the metabolism of total and free prednisolone in 6 renal allotransplanted patients who subsequently developed osteonecrosis of the femoral head and the metabolism of 6 matched controls, who did not develop osteonecrosis. There was no difference in age, bodyweight, total serum protein or albumin, or in liver or renal function. The baseline cortisol was 54 +/- 23 micrograms in patients with necrosis, and 102 +/- 53 micrograms/l in patients without necrosis (n.s.). Likewise there was no difference in the peak concentration of prednisolone (420 +/- 43 vs. 394 +/- 42 micrograms/l, n.s.), the bioavailability (0.57 +/- 0.09 vs. 0.61 +/- 0.05, n.s.) or in the apparent volume of distribution at steady state (Vdss, 0.37 +/- 0.09 vs. 0.37 +/- 0.04 l/kg, n.s.). The clearance of prednisolone in patients with osteonecrosis was 33% lower (0.79 +/- 0.11 vs. 1.18 +/- 0.13 ml/min./kg b.wt., P < 0.05) and t1/2 was correspondingly 33% longer (246 +/- 18 min. vs. 184 +/- 15 min., P < 0.05) than in patients without osteonecrosis. However, there was no difference in the apparent volume of distribution of free prednisolone (2.07 +/- 0.36 vs. 1.69 +/- 0.28 l/kg, n.s.), in the t1/2 (152 +/- 30 vs. 107 +/- 20 min., n.s.), or in the clearance (7.33 +/- 2.12 vs. 7.82 +/- 1.18 ml/min./kg) between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic analysis of steroid-induced osteonecrosis of the femoral head

“…It has been reported that the clearance of prednisolone was 33% lower and its halflife was correspondingly 33% longer in patients with ONF than in those without ONF. 16 Thus, the possibility of steroid accumulation in the body can be considered to cause ONF. Individual differences may be related to single nucleotide polymorphism (SNP) in the DNA sequence of the metabolic enzyme.…”

Pharmacokinetics and Pharmacodynamic Response of Methylprednisolone in Premenopausal Renal Transplant Recipients

“…Prior to methylprednisolone, the baseline serum cortisol concentration ranged from 15.3 to 161 ng/mL. Six of 13 subjects had cortisol concentrations at time 0 and 24 hours in the normal range (80–150 ng/mL) 3 , 16 . The 24hour cortisol concentrations were within 25% of baseline values in 7 of 13 subjects, with a mean concentration of 76.6 ± 55.3 ng/mL.…”

“…Six of 13 subjects had cortisol concentrations at time 0 and 24 hours in the normal range (80-150 ng/mL). 3,16 The 24hour cortisol concentrations were within 25% of baseline values in 7 of 13 subjects, with a mean concentration of 76.6 ± 55.3 ng/mL. Four of 13 had greater cortisol concentrations at time 0 compared to 24 hours, which may be attributed to the stress of catheter placement at study commencement.…”

“…Blood was collected prior to study at approximately 8 AM, followed by a 20-minute intravenous infusion of methyl-prednisolone sodium succinate (Pharmacia/ Upjohn, Lot 21 BKC, Kalamazoo, Mich) in a dose equivalent to the subject's chronic oral dose. Whole blood (7 mL) was obtained for cortisol and methylprednisolone at time 0 and at 0.5, 1, 2, 3,4,6,8,10,12,16,20,22, and 24 hours after drug administration. Adrenocorticotropin hormone (ACTH) samples were collected at time 0 and at 0.5, 1, 4, 8, 12, 20, and 24 hours.…”

“…22 In addi- tion, calcium channel blockers such as verapamil and diltiazem, which are commonly prescribed for transplant recipients, may contribute to the interpatient variability noted due to the inhibitory effect of these drugs on CYP450 3A. 16 We were unable to complete a subanalysis because sufficient male subjects were not receiving these agents comparable to the female group. The influence of race on the pharmacokinetics of methylprednisolone in our female subjects should also be considered (Figure 1).…”