The disposition of valproic acid was studied following single dose intravenous administration in seven young male volunteers aged 20‐35 years and six elderly male in‐patients aged 75‐87 years. Following administration of 400 mg sodium valproate, blood samples were collected for 48 h and valproic acid concentrations analysed by enzymatic immunoassay. The median elimination half‐life was 7.2 h in the young subjects but 14.9 h in the elderly patients (P less than 0.01). However, clearance did not differ significantly between groups, the values for young and old being 0.69 and 0.58 1/h respectively. The prolonged half‐life resulted from a greater volume of distribution in the elderly. The median values (1/kg) for young and old were 0.13 and 0.19 respectively (P less than 0.01). These pharmacokinetic changes are unlikely to be of clinical importance.

I Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. SThe absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P< 0.005), the 5-15% difference between the two formulations should not normally be of any clinical significance.

1 Gentamicin therapy should be guided by serum level monitoring in all age groups, dosage adjustments depending on age related changes in pharmacokinetics. 2 Population data analysed from two centres (43 infants from Glasgow and 100 infants and children from Manchester) by the computer program NONMEM showed that volume of distribution was related to body weight by a proportionality factor that decreased from the region of 0.41-0.46 1/kg in children less than 3 months to 0.25-0.32 1/kg in older children, a value which merges with that accepted for adults (0.25 1/kg). 3 In both young and older children, clearance was also found to be dependent on body weight. Renal function (creatinine concentrations) provided no further explanatory power. 4 When these results were used prospectively to forecast gentamicin concentrations with a Bayesian kinetic parameter estimation program, trough concentrations were more precisely predicted than peaks when a single concentration measurement was used. In clinical practice, however, two concentration measurements are usually routinely available and these should lead to greater precision of both peak and trough predictions. 5 These results have been incorporated into a simple nomogram which can be used to determine a dose of gentamicin which will achieve target peak concentrations in infants, assuming that troughs should not exceed 2 ,ug/ml.

The aim of the study was to determine the absolute bioavailability of orally administered ramelteon (TAK‐375), a novel selective ML1 receptor agonist currently under investigation for the treatment of insomnia and circadian rhythm sleep disorders. Eighteen healthy male subjects received a tablet formulation (16 mg) and a 5‐minute IV infusion (2 mg) of ramelteon during this two‐period crossover study. Blood samples were collected for the analysis of serum ramelteon and metabolites (M‐I, M‐II, M‐III, and M‐IV). The absolute bioavailability of ramelteon, based on the ratio for AUC (0‐ω) (norm) between the tablet and IV formulation, following a single oral dose was very low (<2%). For individual subjects, the absolute bioavailability was variable, ranging from 0.5% to 12%. A previous study with radiolabeled ramelteon has shown that as much as 84% of the orally administered radioactivity was recovered in the urine, mostly as several metabolites, with unmetabolized ramelteon accounting for <0.1 % of the administered dose. These findings indicate that the oral absorption of ramelteon is excellent, but the drug undergoes extensive first‐pass metabolism. Clinical Pharmacology & Therapeutics (2004) 75, P22–P22; doi: