Masato Terakawa

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.

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.

Aldose reductase inhibitory and uricosuric activities of FK366 in healthy volunteers.

The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependency, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half‐life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.