The absorption, distribution, metabolism, and excretion of 3-(N-formylhydroxylamino) propylphosphonic acid monosodium salt (fosmidomycin), a new antibiotic, were investigated in rats and dogs after i.v. and oral dosing. After i.v. administration of 10 mg/kg of body weight, [14C]-fosmidomycin was excreted mainly in the urine (about 90% of dose within 72 h); and only a little was excreted in the expired air (14CO2) and bile of rats (less than 1% of dose), which suggested the absence of enterohepatic circulation. After oral administration of 10 mg/kg of body weight to rats, 34% and 61% of dose were excreted in the urine and faeces, respectively, suggesting about 30% gastro-intestinal absorption. No metabolites were found by autoradiography of the urine after thin layer chromatography. Radioactivity levels in the serum essentially agreed with the unchanged fosmidomycin levels determined by reverse isotope dilution method. [14C]-fosmidomycin was rapidly distributed in the tissues of rats, and was maintained in high concentration in the liver, kidneys, and bone. The serum level data after i.v. administration closely fitted a 3-compartment open model with first order kinetics after nonlinear least squares regression by NONLIN. The half-lives of the serum level curves for the early, midway, and terminal phases were: 0.13, 0.51, and 17.3 h, respectively in rats; and 0.44, 0.75, and 2.0 h, respectively in dogs.
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.
Significant increases of Cmax and ka and reductions of tmax and elimination t1/2 of the inhaled FK706 were observed in the healthy smokers, suggesting that the smoking habit accelerates the drug absorption after inhalation. These results suggest that we should pay attention to the drug-related adverse events caused by smoking, especially when the drug has a narrow therapeutic range.
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.
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 dependently, 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.
FK070, a thromboxane A2 (TXA2) receptor antagonist/TXA2 synthetase inhibitor, was given orally to healthy male volunteers in a single- and multiple-dose study. In the single-dose study (200, 300, 400 mg), the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) increased non-linearly with dose, while the mean elimination half-life (V0) was essentially unchanged (3.9-7.3h). Recovery of the unchanged drug in the urine was 12-25%. Cmax and AUC as determined with 200 mg of drug after a meal decreased by about 60 and 30%, respectively. Ex-vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was almost completely inhibited within 1 h, after all doses of drug, with a significant dose-dependent inhibition maintained for 8 h or more, which was much longer than was expected from drug plasma concentration. The aggregation by adenosine diphosphate (ADP) was inhibited to a lesser extent. FK070 also inhibited TXA2 synthetase as evidenced by decreased production of TXB2 and reciprocally increased production of 6-keto-prostaglandin F1 alpha in the serum during ex-vivo whole blood coagulation. These effects peaked 1 h after drug and lasted until 4 h with the higher doses. In the multiple-dose study (300 mg, twice a day, after meals for 6.5 days), drug concentrations in the plasma were well fitted to a three-compartment open model with first-order absorption. FK070 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, with a significant inhibition lasting as long as 48 h after conclusion of administration. No clearly drug-related changes were found in routine laboratory tests, subjective and objective findings, or vital signs. FK070 was concluded to be well tolerated and to provide long-lasting blockade of TXA2 receptors, and plasma concentration-dependent inhibition of TXA2 synthetase in the platelets.
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