Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.
The pharmacokinetics of intravenous and oral propranolol have been compared in six obese and six normal subjects matched for age and sex. 'After intravenous administration there was no difference in plasma clearance but the volume of distribution was greater (V = 3391 vs 1981) and the half-life was longer (t½/2 T 5.0 h vs 3.0 h) in the obese group. No important difference in the rate of oral absorption was observed. A trend towards higher systemic availability in the obese group (35% vs 27%) was not statistically significant.
Five methods to predict phenytoin dosage have been compared in nine continuous care elderly patients. For each patient three steady-state plasma concentrations were obtained at three different doses. The data were used to estimate the 'optimum' dose for each patient by direct linear plot. The optimum dose for each patient was predicted from each plasma concentration using five dosage prediction methods based on the Michaelis-Menten equation using: (i) the population mean Vmax, (ii) the population mean KM, (iii) the linearized Bayesian method, (iv) the Rambeck nomogram, and (v) two plasma concentration-dose data pairs to estimate both Vmax and KM. The predictive precision was similar for each of methods (i-iv). Ninety-six out of 126 dosage predictions with the five methods were within 25 mg of the optimum dose. Methods (ii) and (iv) tended to overpredict dosage, particularly when used to interpret low plasma phenytoin concentrations.
The plasma and breast milk were sampled from a woman who was breastfeeding whilst taking disopyramide (200 mg three times daily). Paired samples taken on the fifth to eighth day of treatment showed that disopyramide was present in breast milk in a similar concentration to plasma (mean +/‐ s.d. milk; plasma ratio 0.9 +/‐ 0.17). The estimated dose likely to be ingested by an infant is less than 2 mg kg‐ 1 day‐1. The active N‐monodesalkyl metabolite of disopyramide (NMD) although present in plasma in much smaller concentrations than the parent compound, was excreted in breast milk (mean +/‐ s.d. milk: plasma ratio 5.6 +/2.9) in concentrations similar to those of disopyramide. The pharmacological and toxicological properties of the disopyramide metabolite need to be considered when assessing likely effects on the infant. No adverse effects were noted in the infant in this case. Maternal plasma and breast milk were sampled again along with infant plasma after 28 days. Disopyramide and NMD were undetectable in the infant's serum. No evidence was found to indicate that the concentrations of disopyramide or NMD in breast milk might be sufficient to pose a definite risk to the infant. Whenever disopyramide is prescribed in a breast feeding mother, close observation of the baby and measurement of both disopyramide and its active metabolite NMD in breast milk or infant plasma is recommended, pending further investigation.
SUMMARY During therapy with oral controlled released theophylline/aminophylline, steady‐state plasma drug concentrations may be predicted by fitting estimates of patient pharmacokinetic parameters to a pharmacokinetic model. The choice of model requires an assumption about the type of rate reaction of the drug absorption process (zero order or first order). In 10 subjects, plasma theophylline concentrations after a single intravenous dose of aminophylline were used to make individual estimates of drug clearance and volume of distribution. Each subject then received oral controlled release theophylline (‘Theo‐Dur’, Fisons Pharmaceuticals plc) and steady‐state pre‐dose and post‐dose plasma concentrations were determined. Predictions of steady‐state plasma theophylline concentrations using pharmacokinetic models based on first‐order (Model A) and zero order (Model 01) drug absorption were compared. Model A and Model 01 each underestimated the pre‐ and post‐dose steady‐state plasma drug concentrations. However, Model 01 was more accurate in predicting post‐dose drug concentrations, whilst Model A demonstrated better precision in the prediction of pre‐dose drug concentrations at steady‐state (P<0·05).
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