Effect of protein binding of pilsicainide on the pharmacokinetics.

To evaluate the effect of protein binding of pilsicainide on its clearance and the contribution of protein binding to optimized pilsicainide therapy, clinical laboratory and pharmacokinetic data were studied in 160 Japanese inpatients (Study 1) and 18 Japanese inpatients (Study 2). To determine the relation between protein concentration and the protein binding ratio of pilsicainide in vitro, the effect of human alpha1-acid glycoprotein (AAG) and human albumin on the binding ratio was studied. The mean ratio of serum pilsicainide concentration to dose per body weight (C/D) increased with increases in the C-reactive protein (CRP) concentration in Study 1. The AAG level increased with increases in the CRP concentration and the binding ratio increases in the AAG concentration in the Study 2. The binding ratios increased with increased AAG and albumin concentrations; the AAG concentration relative to the ratio was particularly large in vitro study. These results suggest C/D is increased in patients with high CRP levels because of binding of pilsicainide to protein, resulting decreased clearance.

Impairment of ciprofloxacin absorption by calcium polycarbophil.

The effect of calcium polycarbophil on the absorption of ciprofloxacin, a broad-spectrum antibacterial agent, was evaluated in an in vitro and in vivo study. In the in vitro study, the release of ciprofloxacin from the cellulose membrane in the presence or absence of metal cations was measured using the dissolution test procedure. In the in vivo study, male ST Wistar rats and male volunteers were employed. First, 20 mg/kg of ciprofloxacin alone (Rat Study 1) or 20 mg/kg of ciprofloxacin in combination with 64 mg/kg of calcium chloride (Rat Study 2) was administered orally to 3 rats. Second, a volunteer study was employed and a randomized crossover design with twophases was used. In onephase, volunteers received 400 mg of ciprofloxacin alone (Study 1); in the other phase, they received 400 mg of ciprofloxacin and 1200 mg of fine calcium polycarbophil granules concomitantly (Study 2). The plasma and serum concentrations of ciprofloxacin were measured by high-performance liquid chromatography. The release of ciprofloxacin from the cellulose membrane in the presence of aluminum, calcium, or iron ions was slower than that in the absence of these metal ions. The AUC0-4 and Cmax in Rat Study 2 were lower than those respective values in Rat Study 1. AUC0-4 was approximately 60% lower in Rat Study 2 than Rat Study 1. In the volunteer study, the AUC0-12 and Cmax in Study 2 were lower than those respective values in Study 1. In particular, AUC0-12 was approximately 50% lowerin Study 2 than in Study 1. These findings suggest that when ciprofloxacin and calcium polycarbophil were coadministered concomitantly, a decrease of ciprofloxacin absorption was observed, and this action was caused by the formation of chelate complexes. Therefore, it seems clear that we should avoid the concomitant administration of ciprofloxacin and calcium polycarbophil.

Impairment of mycophenolate mofetil absorption by calcium polycarbophil.

The effect of calcium polycarbophil on the absorption of mycophenolate mofetil, an immunosuppressive agent, was evaluated in healthy subjects. In vitro studies were performed to further evaluate the mechanism of the potential interaction. In the in vitro study, the release of mycophenolate mofetil from a cellulose membrane in the presence or absence of metal cations was measured using the dissolution test procedure. In the in vivo study, a randomized crossover design with two phases was used. In one phase, 6 male healthy volunteers received 1000 mg of mycophenolate mofetil alone (treatment 1); in the other phase, they received 1000 mg of mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 2). They received 30 mg of lansoprazole for 5 days and, on the 6th day, received mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 3). The serum concentration of mycophenolic acid was measured by high-performance liquid chromatography. In the in vitro study, the release from a cellulose membrane in the presence of calcium or iron ions was slower than that in the absence of these metal ions. In the in vivo study, the AUC0-12 and C(max) in treatment 2 were less than those in treatment 1. About 50% and 25% decreases in AUC0-12 in treatment 2 and treatment 3 were observed compared with those in treatment 1, respectively. These findings suggest that when mycophenolate mofetil and calcium polycarbophil were coadministered concomitantly, a decrease in mycophenolate mofetil absorption was observed. Therefore, it appears clear that the concomitant administration of mycophenolate mofetil and calcium polycarbophil should be avoided.

Relationship between serum aprindine concentration and neurologic side effects in Japanese.

The aim of this study was to evaluate the relationship between the neurologic side effects associated with serum aprindine concentrations and the safety range of aprindine for the prevention of neurologic side effects in 142 Japanese inpatients. Serum aprindine concentrations were determined by high-performance liquid chromatography. A poor positive correlation was observed between dose and serum aprindine concentration (r(2)=0.0419, p=0.0114), and between age and ratio of serum aprindine concentration to the dose per body weight of aprindine (r(2)=0.0159, p=0.121). When aprindine concentration was <1 microg/ml, almost no patients showed neurologic side effects associated with aprindine. On the other hand, about 50% of the patients showed neurologic side effects when aprindine concentrations were >1 microg/ml. Here, the side effects associated with aprindine such as dizziness or intention tremors were observed in 15 patients, which later disappeared after discontinuance of aprindine therapy or a decrease in the dose. In conclusion, serum aprindine concentration should be maintained under approximately 1 microg/ml in Japanese patients to prevent neurologic side effects.

Effects of serum concentrations of disopyramide and its metabolite mono-N-dealkyldisopyramide on the anticholinergic side effects associated with disopyramide.

The aim of this study was to evaluate the relationship between the anticholinergic side effects associated with disopyramide (DP) and serum DP or mono-N-dealkyldisopyramide (MND) concentrations and the safety range of DP or MND for prevention of anticholinergic side effects in 141 inpatients. The serum DP and MND concentrations were determined by high-performance liquid chromatography. No correlation was observed between creatinine clearance (Ccr) and the ratio of the serum concentration to the dose (C/D) of DP, but a significant inverse correlation was observed between Ccr and the C/D of MND. It was observed that the ratio of MND concentration to DP concentration in the group, whose Ccr was below 20 ml/min, was higher than that of the other groups. Although no significant difference was observed in the DP concentration between the patients without (Group 1) or with (Group 2) anticholinergic side effects, significant differences were observed in the MND concentration, Ccr, and the ratio of MND/DP. The DP concentrations of both Groups 1 and 2 were distributed from 0.13 to about 5 microg/ml. On the other hand, although the MND concentrations of Group 1 were below about 1 microg/ml, the MND concentrations of Group 2 were above about 1 microg/ml. These results suggest that not only DP concentration but also MND concentration should be monitored in patients whose renal function is decreased to prevent anticholinergic side effects associated with DP, and that when serum MND concentration was over approximately 1 microg/ml, the dose should be decreased or discontinued.

Effects of turmeric extract on the pharmacokinetics of nifedipine after a single oral administration in healthy volunteers.

The effects of turmeric extracts on the pharmacokinetics of nifedipine were examined in 10 healthy volunteers. An open-label and randomized crossover study was performed at 2-week intervals. In the control experiment, after a 10 h overnight fast, 10 mg of nifedipine (Adalat® capsule) was administered orally and blood was collected at 0, 0.5, 1, 2, 3, 4, 5, 6, and 8 h. In the combination experiment, the volunteers were orally administered 10 mg of nifedipine together with six tablets containing concentrated turmeric extract (480 mg of curcuminoid per six tablets), which is the general daily dose, and blood was sampled as above. The time profile of the plasma concentration of nifedipine in the control was comparable to that in combination with turmeric extract, as were the pharmacokinetic parameters: that is, the mean ratio of turmeric extract/control group (90% confidence interval: CI); C(max), 0.98 (0.95, 1.01) and AUC(0 - ∞) 1.00 (0.98, 1.02). In addition, the volunteers all completed the study without any serious adverse events. Consumption of the turmeric extract did not affect the pharmacokinetics of nifedipine after a single oral administration.