Pharmacokinetics of midazolam in Vietnamese subjects.

In order to examine the investigators' clinical suspicion that Vietnamese patients were more sensitive to the sedative effects of midazolam than were Caucasians, the pharmacokinetics of a single, weight-adjusted intravenous dose of midazolam (0.05 mg/kg) were compared in a group of healthy Caucasian and Vietnamese male volunteers. The Vietnamese group (n = 8) had a significantly lower height, lean body mass and mean weight (59.8 +/- 5.5 vs 72.1 +/- 8.1 kg, respectively) compared with the Caucasian group (n = 8). No significant differences were found between the Vietnamese and Caucasian groups with regard to distribution half-life of midazolam (8.38 +/- 13.1 vs 1.49 +/- 0.63 min, respectively), elimination half-life (2.49 +/- 1.80 vs 1.48 +/- 0.66 h, respectively), clearance (4.93 +/- 1.31 vs 5.90 +/- 2.12 mL/min per kg, respectively), steady state volume of distribution (0.863 +/- 0.497 vs 0.530 +/- 0.132 L/kg, respectively) or percentage of unbound drug in plasma (4.89 +/- 0.74 vs 4.11 +/- 1.08, respectively). This suggests that dosage of midazolam in Vietnamese should be based on total bodyweight. Two Vietnamese subjects who were brothers had marked elevation of distribution half-life and initial volume of distribution and lesser elevations in elimination half-life and volume of distribution at steady state. This suggests that the known subgroup of subjects who demonstrate dyshomogeneity in midazolam volume of distribution may be genetically determined.

Influence of albumin on isoprenaline and propranolol effects on isolated rat uterus.

We investigated the effect of albumin (6%) on the (+/-)-isoprenaline-induced relaxation of strips of isolated rat uterus and its antagonism by (-)-propranolol. The mean isoprenaline EC50 in the presence of albumin was significantly less than that in the absence of albumin (geometric mean 1.94 +/- 3.33 versus 3.21 +/- 3.50 nM, respectively; n = 14; p = 0.006, paired t test). This indicates enhancement of isoprenaline activity by albumin which could not be explained by protein binding, as this would have reduced activity. Geometric mean control KB values for inhibition of isoprenaline by propranolol at 26.8 and 500 nM were 0.835 +/- 1.68 (n = 10) and 0.889 +/- 1.60 nM (n = 34), respectively. In the presence of 6% albumin, KB for propranolol was increased significantly to 13.3 +/- 1.8 nM (n = 27, p < 0.001). Calculation of KB in terms of the measured propranolol unbound concentration of 26.8 nM, after taking into account the lower isoprenaline EC50 in the presence of albumin, yielded a mean value of 0.725 +/- 1.86 nM, which was not significantly different from either control (p > 0.05). Therefore, propranolol activity was as predicted by the unbound drug concentration in contrast to isoprenaline activity. We conclude that albumin can alter in vitro drug activity by mechanisms in addition to the reduction of unbound drug concentration.

Pharmacokinetics of intravenous and oral salbutamol and its sulphate conjugate.

The pharmacokinetics of salbutamol and its sulphate conjugate metabolite were investigated after intravenous and steady-state oral administration of salbutamol to 10 healthy volunteers. With intravenous administration, total plasma clearance was 480 +/- 123 ml min-1, elimination half-life was 3.86 +/- 0.83 h and apparent volume of distribution was 156 +/- 381. Urinary excretion of unchanged drug and sulphate conjugate were 64.2 +/- 7.1% and 12.0 +/- 3.1% of the dose, respectively. With oral administration, systemic availability was 0.50 +/- 0.04, and urinary excretion of unchanged drug and sulphate conjugate were 31.8 +/- 1.9% and 48.2 +/- 7.3% of the dose, respectively. The drug eliminated on the first-pass could be accounted for entirely as sulphate conjugate formed, presumably, in the intestinal wall. Renal clearance of salbutamol was 291 +/- 70 ml min-1 after intravenous and 272 +/- 38 ml min-1 after oral administration, while the renal clearance of the sulphate conjugate was 98.5 +/- 23.5 ml min-1 after oral administration. Heart rate increased with increasing plasma salbutamol concentration, although a lag was evident. The effect on heart rate was lower after 24 h continuous oral salbutamol administration.