Processes controlling the absorption, distribution, metabolism, excretion, and pharmacologic effects of drugs are likely to be immature or altered in neonates and infants. Absorption may be affected by differences in gastric pH and stomach emptying rate. Low serum protein concentrations and higher body water composition can change drug distribution. Drug metabolism enzyme activity is typically reduced in the neonate, but rapidly develops over the first year of life. Renal excretion mechanisms are low at birth, but mature over a few months. Limited data are available on the pharmacodynamics of drugs; infants show greater sensitivity to d-tubocurarine. Developmental changes are rapid during the first weeks and months of life, thus requiring continual modification of drug dosage regimens designed for treating pediatric patients.
Obesity is accompanied by altered secretion and disposition of sex and glucocorticoid hormones, including cortisol, and also confounds parameter normalization and drug dosage selection relative to body weight. Prednisolone disposition was assessed in eight obese and four normal male subjects after a dose of 33 mg iv. Steroid concentrations were determined by HPLC. Kinetics were related to ideal body weight (IBW) and total body weight (TBW). Uncorrected steady-state volume of distribution (Vss) of total prednisolone was 20% greater in obese subjects (36.7 and 44.1 l). This effect could be described by the relationship: Vss = 0.54 IBW + 0.09(TBW-IBW), with a distribution coefficient of 0.09 reflecting limited prednisolone uptake by fat. Protein binding parameters and albumin and transcortin concentrations were similar between groups. Uncorrected total and free prednisolone clearances (Cl) were increased in obesity (11.1 and 8.3 l/hr total; 65.4 and 46.5 l/hr free). Free prednisolone Cl correlated strongly (r = 0.80) with degree of obesity expressed as TBW/IBW. In the obese, endogenous cortisol concentrations were initially higher before exogenous steroid dosing, were suppressed at an identical rate, and returned to baseline more slowly than in normal subjects. The apparent hypersensitivity of the adrenal gland offsets the increased Cl of free prednisolone in obesity, indicating that weight-proportional dosage adjustments of this steroid in obesity should reflect TBW.
The pharmacokinetics and bioavailability of prednisolone after doses of oral prednisone and intravenous prednisolone were determined in seven patients receiving corticosteroids for treatment of inflammatory bowel disease in active disease and remission. Prednisone absorption and conversion to the active form of prednisolone was complete in both disease phases. Pharmacokinetic parameters for total and free (unbound) prednisolone did not differ significantly between disease phases. Differences in protein binding were observed between active disease and remission with the fractional binding of prednisolone to plasma proteins decreased in active disease. This may be accounted for by decreased plasma albumin concentrations in active disease. Alpha 1-acid glycoprotein concentrations were significantly higher in active disease but did not contribute to the overall binding of prednisolone.
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