小児期に於ける血中プレドニゾロン代謝の特徴に関する研究:第二編 薬用量及び維持用量投与下の血中濃度からみた, 小児期各病態に於ける, プレドニゾロンの吸収・代謝について
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Pharmacokinetics of prednisolone (PSL) were studied in overnight-fasted children following iv. and oral dosage of PSL or PSL-21-hemisuccinate sodium solution (PSL-HS-Na). The evaluation were performed in the aspect of the physiological or pathological influences on plasma PSL metabolism and the effects of plasma PSL metabolism on the hypothalamo-pituitary-adrenal (HPA) axis. The result were as follows.<BR>1. A good correlationship (r=0.92, p<0.001) between plasma peak value (Cp) and single oral dosage was obtained. 2. The dietary (milk 200ml) effect lowered Cp (p<0.001), prolonged late half-life (Tb), and remained unchanged in the area under the concentrationtime curve (AUC) divided by dosage (mg/kg or mg/m2) (unit dosage). 3. Pharmacokinetic studies on five adult volunteers after single 2.5% PSL ethanol iv. administration resulted 83±11 (l/m2/day) in the metabolic clearance rate (MCR), 4.8±0.6 (l/m2) in the central distribution volume (Vc), 5.5 ± 4.0 (l/m2) in tissue compartment of Vc (Vt), and 1.77 ± 0.2 (hr) in Tb. 4. Information obtained from the plasma monitoring after a single oral (lmg/kg) dosage in 20 children and adult controls, who were normal as far as PSL-metabolism, were analyzed for the physiological effect on PSL metabolism. The lower Cp(p<0.01-001), the lower AUC/unit dosage (p<0.01-0.001), higher MCR (p<0.1-0.05) under the 10y/o group, and the longer Tb (p<0.1) in the 1-5y/o group than in the adult group were found statistically in children, which may represent clinically poor absorption, high metabolism and a large distribution volume in children, This may be the reason why the dosage requirement in children of PSL is sometimes greater when the drug is given orally. In contrast, no differences were found between the adult group and in the group after 10y/o, which suggests that PSL metabolism and absorption is developing and maturing. 5. The studies of plasma PSL metabolism under several pathological conditions indicated low Cp, low AUC/unit dosage, slightly high MCR in nephrotic syndrome, prolonged Tb in liver disease, low Cp with low AUC/unit dosage in protein-losing enteropathy, prolonged Tb, increased Vc, low MCR in bilateral nephrectomized rats and cardiac-failed dogs with bilateral femoral A-V bypass operation. 6. Simultaneous monitoring on blood ACTH, cortisol (F), 17-OH-progesterone (17 OHP) and PSL were performed in 14-adrenal disorders in order to investigate PSL-maintenance dosage-effect on the HPA axis. Three patterns of response to PSL in HPA suppression were divided in various ways, such as good suppression with normal PSL levels (n=10, 53 ± 7ng/ml), poor suppression with poor PSL levels (n= 2;33, 35ng/ml), poor suppression with normal PSL levels (n=2;5 0, 57ng/ml). One of the second pattern-cases improved after a double dosage to good suppression with good PSL levels (57ng/ml). These findings suggest that plasma PSL levels around 40-50ng/ml may be the borderline level in HPA suppression. Upon analyzing these poor responders, half of them showed poor intestinal absorption, while another half of them suggested some ab-normality in HPA regulation mechanism. One case of 21-OH-lase deficiency developed another pattern of insufficient suppression of HPA aixs after a single oral F-maintenance dosage (10mg/m2/dose), (poor suppression of 17 OHP with good suppressed ACTH and normal F level (382ng/ml)), which showed it was important for the evaluation of HPA suppression to know the adrenal condition (adrenal hyperplasia, etc.). To monitor plasma PSL levels, if the individual PSL-adsorption and metabolism may be influenced by physio-logical and pathological factors, it is important and useful to know the achievement of PSL treatment, especially in children.
- 一般社団法人 日本内分泌学会の論文