Susumu Ohshiro

Rapid and simple micro-determination of carvedilol in rat plasma by high-performance liquid chromatography

We studied the use of high-performance liquid chromatography (HPLC) with spectrofluorometric detection, using a solid-phase extraction for a simple, rapid and sensitive determination of plasma carvedilol levels in rats. Extracted aliquots were analyzed by HPLC, using a reversed-phase octadecyl silica column. The analytical mean recovery of carvedilol added to the blank plasma was 94.2%. The detection limit was 3.6 ng/ml in the plasma. The reproducibilities (C.V.) were 2.7-7.5% for the within-day assay, and 2.6-7.4% for the between-day assay, indicating that the method was effective for the determination of carvedilol plasma levels.

Rapid and simple determination of fleroxacin in rat plasma using a solid-phase extraction column.

We studied the use of high-performance liquid chromatography (HPLC) with a spectroflurometric detector, using a solid-phase extraction column (Bond Elut cartridge column), for the simple, rapid and sensitive determination of plasma fleroxacin (FLRX) levels in rats. Extracted aliquots were analyzed by HPLC, using a reverse phase octadecyl silica column. The analytical mean recovery of FLRX added to the blank plasma averaged 101.4%. The detection limit was 58 ng/ml in the plasma. The reproducibilities (C.V.) were 0.50-3.22% in the within-day assay and 2.87 C.V.% in the between-day assay, indicating that the analysis method was effective in the determination of FLRX plasma levels.

Influence of nicardipine and nifedipine on plasma carvedilol disposition after oral administration in rats

The effect of two kinds of 1,4‐dihydropyridine calcium‐channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid‐phase extraction and high‐performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration‐time curve up to 24 h (AUC0→24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg−1 carvedilol with 40 mg kg−1 nicardipine hydrochloride, or with 40 mg kg−1 nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium‐channel blockers is thought to be attributable to vasodilator‐induced changes in hepatic first‐pass metabolism, inhibition in the absorption barrier by P‐glycoprotein and in the metabolism of carvedilol.

Possible mechanisms of low levels of plasma valproate concentration following simultaneous administration of sodium valproate and meropenem

Drug interaction between meropenem (MEPM), a carbapenem of antibiotic agent, and sodium valproate (VPA), an anticonvulsant, was studied in rats and human volunteers. When sodium VPA and MEPM were administered simultaneously, the plasma VPA level was significantly lower and the blood cell/plasma VPA concentration ratio was significantly higher than after the administration of sodium VPA alone (control). Following the simultaneous administration of sodium VPA and MEPM, the pharmacokinetic parameters such as plasma VPA, volume of distribution (Vd) and clearance (CL) were significantly increased, while the maximum plasma concentration (Cmax) and area under the plasma concentration- time curve (AUC) till 3 h were significantly decreased. The ratio of free (unbound) VPA to protein-bound VPA was significantly increased after the administration of MEPM. The concentration of VPA in brain tissue was significantly decreased after the simultaneous administration of VPA and MEPM. Competition between VPA and MEPM for a protein binding site resulted in increased plasma levels of free (unbound) VPA, which then distributed to various tissues, in particular, the blood cells, liver and kidney. VPA which distributed to the liver was metabolized there and excreted. Subsequently, the levels of VPA in the plasma and brain would be significantly decreased.

Effects of salicylate on the pharmacokinetics of valproic acid after oral administration of sodium valproate in rats

- Effects of salicylate on the pharmacokinetics of valproic acid (VPA) after oral administration (p.o.) of sodium valproate were investigated in rats. When salicylic acid was administered orally after sodium valproate p.o., the plasma VPA concentrations including maximum plasma concentration (C max ), area under the plasma concentration-time curve up to 3 h (AUC 0-3 ) and the elimination half-life ( t 1/2 ) of VPA were lower than control values. In addition, when salicylate was administered intraperitoneally or intravenously, the plasma VPA concentrations, AUC 0-3 and t 1/2 of VPA were lower than those in the control group. These results suggest that decreases in the plasma VPA concentrations including C max and AUC 0-3 with simultaneous oral administration of sodium valproate and salicylic acid may be related to both reduction of absorption and increase in clearance of VPA.

Investigation of low levels of plasma valproic acid concentration following simultaneous administration of sodium valproate and rizatriptan benzoate

Drug interaction between rizatriptan benzoate, an anti‐migraine agent, and sodium valproate (VPA‐Na), an anticonvulsant, was studied in rats. When rizatriptan benzoate was administered orally immediately after VPA‐Na oral administration, the pharmacokinetic parameters, such as plasma valproic acid (VPA) and area under the plasma concentration‐time curve up to 3 h (AUC0–3), were significantly decreased compared with those in the control group. However, when rizatriptan benzoate was administered intraperitoneally immediately after VPA‐Na orally, these parameters were not changed. In addition, when benzoic acid was administered orally immediately after VPA‐Na orally, these were significantly lower compared with the control values. Therefore, it might be possible that VPA transport by monocarboxylate transporter was competitively inhibited by rizatriptan benzoate and thus absorption of VPA was decreased.

The Dose-Dependent Pharmacokinetic Interaction between Carvedilol and Amlodipine in Rats.

The pharmacokinetic interaction between carvedilol, a nonselective β-blocking agent and amlodipine besilate, a dihydropyridine calcium-channel blocker were investigated in rats. To determine the concentration-time profile of plasma carvedilol, blood samples were obtained from the tail vein after the oral administration of carvedilol either with or without amlodipine besilate. The plasma carvedilol concentrations and pharmacokinetic parameters, comprising the area under the concentration-time curve from 0 to 24 hours (AUC0-24) showed no changes after the simultaneous oral administration of 20 mg/kg carvedilol and 5 mg/kg amlodipine besilate. In contrast, the plasma carvedilol concentrations at 6 hr-12 hr and AUC0-24 after the oral administration of carvedilol with 40 mg/kg amlodipine besilate were significantly higher than those without amlodipine besilate.These results suggested the pharmacokinetic interaction between carvedilol and amlodipine to be dependent on the dose of amlodipine.

Plasma Valproate Concentration after Simultaneous Administration with Faropenem Sodium in Rats.

The drug interaction between sodium valproate (VPA), an anticonvulsant, and faropenem sodium (FRPM), a new penem antibiotic drug, was studied in rats. No significant change was observed in the plasma VPA concentration when compared with the control after the administration of VPA (TOO mg/kg per oral) simultaneously with FRPM (600 mg/kg per oral).

Study of the Preparation of Fibronectin Eyedrops.

Fibronectin FN) eyedrops, which has been reported to facilitate healing trophic ulcer and recurrent corneal erosion, is usually prepared from 10ml volume of patients own blood.Themethod for the preparation of this eyedrops was studied by determination of FN content.The results were as follows:1) From 20ml volume of blood, double concentration of FN in eyedrops could be made, or a couple of eyedrops could be done at a time.2) FN concentration in eyedrops and area under the curve (AUC) of FN fraction had a good correlation (Y=72.2X-8.7, r=0.979, p<0.01, N=22).Therefore, it was possible to estimate FN concentration in eyedrops from AUC.3) FN was almost lost after sterilization by filtration with nitrocellulose or mixed esters of cellulose membrane.On the other hand, FN almost remained after sterilization by filtration with polyvinylidene fluoride and acetylcellulose membrane.

Compatibility of Berotec Syrup in combination with other liquids. (II). Effect of simple syrup dilution.

The effect of simple syrup dilution in Berotec ® Syrup with other liquids was investigated with regard to changes in appearance and pH value. These changes were tested immediatly and 3 and 7 days after admixing at 30°C and 5°C. The decrease of redistribution occured in admixture with Pontal® Syrup and Asverin® Syrup. A cotton-like substance was observed in all cases of admixtures tested within 7 days at 30°C and identified by IR Spectrum UV Spectrum and high-performance liquid chromatography as Hydroxypropylmethylcellulose (HPMC) which was the additive in Berotec® Syrup.