Yoji Tokuma

Pharmacokinetics of Nilvadipine in Healthy Volunteers

The pharmacokinetics of nilvadipine, a new antihypertensive and antianginal drug, were examined in healthy male volunteers. In a Latin square, three‐way crossover design with a one‐day run‐in period, six subjects in three groups of two each were given single 2‐, 4‐, or 6‐mg oral doses of nilvadipine after overnight fasting. Nilvadipine plasma concentrations up to 32 hours after drug treatment were determined by capillary column gas chromatography‐negative‐ion chemical ionization mass spectrometry (detection limit, 0.01 ng/mL). Nilvadipine urinary concentrations were determined by capillary column gas chromatography with electron capture detector (detection limit, 0.5 ng/mL). Nilvadipine plasma concentrations declined in a bi‐ or triexponential pattern after reaching the maximum plasma concentrations. The mean ± standard deviation maximum plasma concentrations of 1.48 ± 0.47, 3.48 ± 0.53, and 6.69 ± 1.54 ng/mL were attained from 1.08 to 1.50 hours after doses of 2, 4, and 6 mg, respectively. The elimination half‐life was dose‐independent and averaged 11.0 ± 2.3 hours. The area under the plasma concentration‐time curve increased in proportion to the dose. Nilvadipine was not detected in the urine. The pharmacokinetics of nilvadipine were generally linear over the dosage range studied. Besides the above model‐independent pharmacokinetic parameters, model‐dependent parameters were also obtained by curve‐fitting the plasma data to a bi‐ or triexponential equation with zero‐order absorption. Nilvadipine decreased blood pressure slightly and in a dose‐dependent fashion.

Nilvadipine as a neuroprotective calcium entry blocker in a rat model of global cerebral ischemia. A comparative study with nicardipine hydrochloride

The effects of two dihydropyridine type calcium entry blockers, nilvadipine and nicardipine hydrochloride (nicardipine), on the liberation of free fatty acids (FFAs) were investigated using an experimental model of global cerebral ischemia in rats, and were compared with their pharmacokinetic properties. Nilvadipine, but not nicardipine, at a dose of 100 micrograms/kg i.v., significantly attenuated the liberation of FFAs, particularly docosahexaenoic and arachidonic acid. Furthermore, the brain concentration of nilvadipine was higher than that of nicardipine after equivalent dosing. The results of the present study demonstrate that pharmacokinetic differences between these two calcium entry blockers might explain the difference in their pharmacological efficacy.

Determination of nilvadipine in human plasma by capillary column gas chromatography—negative-ion chemical-ionization mass spectrometry

A highly sensitive and specific method for the determination of nilvadipine, a new dihydropyridine calcium antagonist, in human plasma is described. A deuterated analogue of nilvadipine is added to the plasma as an internal standard. The agent and its internal standard are extracted at pH 9 from the plasma into a benzene--n-hexane (1:1) mixture. The extract is analysed by fused-silica capillary column gas chromatography--negative-ion chemical-ionization mass spectrometry with methane as the reagent gas. The mass spectrometer is set to monitor the negative molecular ions of the agent and internal standard. Quantitation is possible down to 0.01 ng/ml using 1 ml of plasma. The coefficients of variation of the method are 6.4 and 2.1% at the 0.01 and 0.1 ng/ml levels, respectively. Plasma levels obtained with this method are given for four healthy volunteers who had received a 6-mg oral dose of nilvadipine.

Multiple‐Dose Pharmacokinetics of Nilvadipine in Healthy Volunteers

Nilvadipine, a new antihypertensive and antianginal drug, was studied in six healthy male volunteers to evaluate its steady‐state pharmacokinetics after oral dosing. The subjects were given a single dose of 4 mg, followed by 4 mg every 12 hours for six days after a washout period of more than 3 days. The pharmacokinetics of nilvadipine were well described by a linear model of triexponential equation with zero‐order absorption. The steady state was reached by the fourth day of multiple dosing, with a twofold accumulation of trough plasma concentration and no accumulation of peak concentration. The mean plasma concentration at steady state was 1.0 ng/mL. The optical enantiomers of nilvadipine were also determined in the plasma. The plasma concentration of (+)‐nilvadipine was about two and a half times higher than that of (‐)‐nilvadipine, and this ratio was unaffected by multiple dosing.

Determination of a new orally active cephalosporin in human plasma and urine by high-performance liquid chromatography using automated column switching

A sensitive method for the determination of a new cephalosporin in human serum and urine is described. The sensitivity of the procedure is derived from a high-performance liquid chromatographic separation which utilizes the different selectivities of two columns. Partial separation of the agent from deproteinized serum or diluted urine is achieved by an anion-exchange column. To concentrate the large volume of the eluent fraction containing the compound from the anion-exchange column, a reversed-phase short column is placed between the anion-exchange column and a reversed-phase analytical column. The separation is completed by switching the eluent fraction containing the compound from the second column to the analytical column. The compound is detected by ultraviolet absorption at 295 nm. Quantitation is possible down to 0.05 microgram/ml using 300 microliter of serum and down to 0.5 microgram/ml using 50 microliter of urine. The coefficients of variation of the method are 6.8% and 0.6% in serum when spiked at the 0.05 microgram/ml and 1.0 microgram/ml level, respectively. One assay can be completed in 16 min. Serum levels and urinary excretion data obtained with this method are given for three healthy volunteers who had received a 100-mg oral dose of the compound.

Effect of Two Different Meals on Bioavailability of Nilvadipine in Healthy Volunteers

The effect of two different meals on the bioavailability of nilvadipine, a new antihypertensive and antianginal drug, was examined in 16 healthy male volunteers in two separate studies. In each study of eight subjects in a Latin‐square, two‐way crossover design, two groups of four subjects each were given a single 6‐mg oral dose of nilvadipine after overnight fasting or 30 minutes after a 464‐ or 748‐kcal meal. There were no significant differences in the area under the plasma concentration‐time curve or the maximum plasma concentration between the fasting and fed states for either meal. Although the time to reach the maximum plasma concentration was about the same after a 464‐kcal meal and after fasting, it increased slightly but significantly after a 748‐kcal meal, indicating possible delay in drug absorption after meals. These studies showed that the extent of bioavailability of nilvadipine appears to be little affected in the presence of food. Although a possible delay in the onset of absorption would occur, such a delay may not have any therapeutic importance in chronic therapy.

High-performance liquid chromatographic determination of prifinium quaternary ammonium ion in human serum and urine

A simple, sensitive method for the determination of the prifinium ion, a quaternary ammonium ion, in human serum and urine is described. The method is based on extraction of the test solution with chloroform in the presence of saturated potassium bromide solution and normal-phase high-performance liquid chromatography using aqueous methanol as the mobile phase at pH 10. To prevent the dissolution of silica from the analytical column, the mobile phase is pre-saturated with silica by using a silica saturation column. Quantitation is possible down to 0.5 ng/ml of prifinium ion using 2 ml of serum and down to 5 ng/ml using a 1 ml of urine. The coefficients of variation of the method are less than 1.3% in both serum and urine. Serum levels and urinary excretion data obtained with this method are given for three healthy volunteers who had received a 60-mg oral dose of prifinium bromide.