Eiji Owada

Effects of diltiazem on plasma level and urinary excretion of digoxin in healthy subjects

To evaluate a possible effect of diltiazem hydrochloride (DTZ) on digoxin (DX) kinetics, we performed a study in which a single oral dose of DX (0.5 or 0.75 mg) was given with and without DTZ (30 mg three times daily for 1 wk) to six healthy subjects. DTZ increased plasma DX concentrations at 3, 4, 6, and 12 hr and decreased renal clearance of DX from 3.05 ± 0.126 to 2.31 ± 0.234 ml/min/kg. There was no significant change in absorption t½, peak concentration, peak concentration time, distribution t½, biologic elimination t½, or apparent volume of distribution with DTZ.

Simple, rapid and sensitive reversed-phase high-performance liquid chromatographic method for the determination of mefenamic acid in plasma

Measurement of plasma levels mefenamic acid MA by a high-performance liquid chromatographic method adapted for monitoring plasma MA in infants between sub-therapeutic and overdose levels using a small amount of plasma

Pharmacokinetics of mefenamic acid in preterm infants with patent ductus arteriosus

The pharmacokinetics of mefenamic acid (MA), 2 mg/kg, were studied in 17 preterm infants with symptomatic patent ductus arteriosus. They were given this dosage orally at 24 h intervals. There were marked inter‐individual differences in some of the pharmacokinetic parameters after the first dose; peak plasma concentration (Cmax) varied from 1.2 to 6.1 μg/mL with a mean of 3.8 μg/mL, time to reach Cmax (tmax) varied from 2 to 18 h with a mean of 7.7 h and plasma half‐life (t1/2) varied from 3.8 to 43.6 h with a mean of 18.7 h. The group of infants (10/17) who had ductus closure after the first dose had significantly lower clearance (P < 0.01), longer t1/2 (P < 0.01) and higher 24h plasma concentration (P < 0.001) compared to the group of infants (7/17) who had no ductus closure after the first dose. It appeared that the plasma concentration of MA had to be above 2.0 μg/mL and maintained at this concentration for at least 12 h for MA associated with ductus closure in preterm infants to take effect. In view of the inter‐individual variation of plasma MA concentration and the effective plasma concentration, we suggest that measurement of the plasma concentration should be done 24 h after the first dose. This might be useful for safe and effective therapy for infants with ductus closure failure after the first dose.

Nonlinear elimination of benzoate in patients with congenital hyperammonemia

Sodium benzoate is effective for treatment of hyperammonemia caused by inborn errors of urea synthesis) -4 Although previous reports ~, 2 have suggested that relatively large doses of benzoate can be tolerated without toxicity, Sorrie adverse effects, 3,4 including death, were reported at higher doses. At present, however, there is little information concerning the blood elimination kinetics of benzoate. We studied the pharmacokinetics of benzoate in two patients with hyperammonemia.

Determination of streptomycin in serum by high-performance liquid chromatography

A high-performance liquid chromatographic method was developed for monitoring the serum concentration of streptomycin. The method includes clean-up using a Sep-Pak C18 cartridge and quantitation using dihydrostreptomycin as an internal standard. Streptomycin and dihydrostreptomycin were separated by reversed-phase ion-pair chromatography on LiChrosorb RP-18 and detected by UV absorption (195 nm). The calibration graph of serum streptomycin concentration was linear over the range 5-50 micrograms/ml. Streptomycin was added to serum at the level of 20.0 micrograms/ml and its concentration was determined to be 18.9 micrograms/ml with a coefficient of variation of 2.07% (n = 5). The clinical application of this method was confirmed by comparison with fluorescence polarization immunoassay.

[Absorption and first-pass-effect of salbutamol after intraduodenal and intrarectal administration in rabbits].

To understand the previous result of higher bioavailability of rectal salbutamol (SB) compared with oral SB, in situ experiments using rabbit duodenal and rectal loop were carried out. After the intravenous (i.v.) and intraportal (i.p.) dosing of SB, fraction of dose which avoids the hepatic first-pass-effect (Fh) was calculated from the areas under the blood concentration-time curve (AUC). The Fh was about 10% and unchanged significantly with increasing i.p. dose (5-20 mg). Intraduodenal (i.d.) or intrarectal (i.r.) dosing of SB was made after the i.v. and i.p. dosing, and the AUCs and the residual amount in the loop were obtained to estimate the parameters. The results of the i.d. and i.r. dosing were as follows; for the extent of bioavailability (EBA), 7.7 +/- 1.5% and 14.5 +/- 2.3%, for the fraction of dose absorbed (fa), 93.9 +/- 3.7% and 33.8 +/- 3.3%, and for the fraction of absorbed SB which avoids first-pass-effects (F), 8.4 +/- 1.9% and 43.0 +/- 6.0% (mean +/- S. E., n = 4). Consequently, SB dosed i.d. was absorbed completely, and received first-pass-metabolism in the mucosa (about 20%) and then in the liver (about 90%), which caused the low bioavailability. While, in i.r. dosing, SB absorption was poor. However, higher bioavailability was obtained owing to about 40% of rectal venous blood flow which bypasses the liver and negligible first-pass-metabolism in the mucosa (about 4%).