研究者詳細 - 大谷　壽一

論文 - 大谷　壽一

分割表示 206 件中 181 - 200 件目／全件表示 >>

Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells

Ikegawa T., Ushigome F., Koyabu N., Morimoto S., Shoyama Y., Naito M., Tsuruo T., Ohtani H., Sawada Y.

Cancer Letters （Cancer Letters） 160 （ 1 ） 21 - 28 2000年11月

ISSN 03043835

We investigated the effects of the ethyl acetate extract of grapefruit juice (GFJ), that of orange juice (OJ) and their components on the uptake of [3H]vincristine into adriamycin-resistant human myelogenous leukemia cells. Its uptake was increased by the extracts of GFJ and OJ up to 7- and 3-fold, respectively, as well as verapamil and cyclosporin A. OJ components, i.e. 3,3',4',5,6,7,8-heptamethoxyflavone, nobiletin and tangeretin, also increased the uptake of [3H]vincristine in a concentration-dependent manner. Although GFJ components, dihydroxybergamottin and bergamottin, significantly increased the uptake, their potencies were considerably weaker than those of OJ components. These data suggest that OJ components inhibit P-gp-mediated efflux of [3H]vincristine, resulting in the intracellular accumulation of chemotherapeutic drugs. These components may become candidates of multi-drug resistance reversing agents in cancer chemotherapy. Copyright (C) 2000 Elsevier Science Ireland Ltd.

Access to Document (DOI)

Propiverine-induced Parkinsonism: A case report and a pharmacokinetic/pharmacodynamic study in mice

Matsuo H., Matsui A., Nasu R., Takanaga H., Inoue N., Hattori F., Ohtani H., Sawada Y.

Pharmaceutical Research （Pharmaceutical Research） 17 （ 5 ） 565 - 571 2000年07月

ISSN 07248741

Purpose. We present a case report of propiverine-induced Parkinsonism. We previously reported the induction of catalepsy by amiodarone, aprindine and procaine, which possess a diethylaminomethyl moiety and demonstrated selective blockade of dopamine D2 receptors by these drugs in mice. We hypothesized that drugs possessing a diethylaminomethyl structure may generally induce Parkinsonism and/or catalepsy. Methods. Thus, we performed a study to examine whether oxybutynin, pentoxyverine and etafenone, as well as propiverine, induce catalepsy in mice. Results. The intensity of drug-induced catalepsy was in the order: haloperidol > etafenone > pentoxyverine > propiverine > oxybutynin. In vivo occupancy of dopamine D1, D2 and mACh receptors in the striatum was also examined. The in vitro binding affinities to the D1, D2 and mACh receptors in the striatum synaptic membrane were within the ranges of 2.4-140 μM, 380-4,200 nM, and 1.2-2,800 nM, respectively. Conclusions. These results support the idea that any drug possessing a diethylaminomethyl moiety may contribute to the induction of catalepsy, possibly by occupying dopamine receptors.

Access to Document (DOI)

Effect of bioflavonoids on vincristine transport across blood-brain barrier

Mitsunaga Y., Takanaga H., Matsuo H., Naito M., Tsuruo T., Ohtani H., Sawada Y.

European Journal of Pharmacology （European Journal of Pharmacology） 395 （ 3 ） 193 - 201 2000年05月

ISSN 00142999

Several grapefruit juice bioflavonoids, including quercetin, are reported to stimulate P-glycoprotein-mediated drug efflux from cultured tumor cells. To see whether these bioflavonoids alter the permeation of vincristine across the blood-brain barrier, we conducted experiments with cultured mouse brain capillary endothelial cells (MBEC4 cells) in vitro and ddY mice in vivo. The steady-state uptake of [3H]vincristine by MBEC4 cells was decreased by 10 μM quercetin, but increased by 50 μM quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [3H]vincristine in ddY mice was decreased by coadministration of 0.1 mg/kg quercetin, but increased by 1.0 mg/kg quercetin. Kaempferol had a similar biphasic effect on the in vitro uptake of [3H]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [3H]vincristine uptake in the 10-50 μM range, and glycosides (hesperidin, naringin, rutin) were without effect. We then addressed the mechanism of the concentration-dependent biphasic action of quercetin. Verapamil, a P-glycoprotein inhibitor, inhibited the efflux of [3H]vincristine from MBEC4 cells, while 10 μM quercetin significantly stimulated it. The uptake of [3H]vincristine by MBEC4 cells was increased by inhibitors of protein kinase C, but decreased by phorbol 12-myristate-13- acetate (PMA), as well as by 10 μM quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 μM quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5- isoquinolinesulfonyl)-2-methylpiperazine, 30 μM). We conclude that low concentrations of quercetin indirectly activate the transport of [3H]vincristine by enhancing the phosphorylation (and hence activity) of P- glycoprotein, whereas high concentrations of quercetin inhibit P- glycoprotein. Our results indicate that patients taking drugs which are P- glycoprotein substrates may need to restrict their intake of bioflavonoid- containing foods and beverages, such as grapefruit juice. (C) 2000 Elsevier Science B.V.

Access to Document (DOI)

Induction of apoptosis in mouse brain capillary endothelial cells by cyclosporin A and tacrolimus

Kochi S., Takanaga H., Matsuo H., Ohtani H., Naito M., Tsuruo T., Sawada Y.

Life Sciences （Life Sciences） 66 （ 23 ） 2255 - 2260 2000年04月

ISSN 00243205

Although cyclosporin A and tacrolimus are used clinically as potent immunosuppressants, there have been reports of neurotoxicity and encephalopathy. A possible mechanism is that these drugs damage the blood- brain barrier (BBB), inducing dysfunction and increased permeability, and are then able to enter the brain. We studied the cytotoxicity of cyclosporin A and tacrolimus, focused on apoptosis induction, using an immortalized cell line established from BALB/c mouse cerebral microvessel endothelial cells (MBEC4). We found that these two drugs induced cell shrinkage, chromatin condensation and DNA fragmentation, which are characteristics of apoptosis. Our data suggest that the induction of apoptosis on the brain capillary endothelial cells may be at least partly involved in the occurrence of immunosuppressant-induced encephalopathy.

Access to Document (DOI)

Polymethoxylated flavones in orange juice are inhibitors of P- glycoprotein but not cytochrome P450 3A4

Takanaga H., Ohnishi A., Yamada S., Matsuo H., Morimoto S., Shoyama Y., Ohtani H., Sawada Y.

Journal of Pharmacology and Experimental Therapeutics （Journal of Pharmacology and Experimental Therapeutics） 293 （ 1 ） 230 - 236 2000年04月

ISSN 00223565

The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [3H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [3H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 μM), an inhibitor of P-gp. No significant effect on the uptake of 3-O- [3H]methylglucose or [14C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [3H]vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8- heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [3H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 μM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6β-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [3H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.

Determination of erythromycin, clarithromycin, roxithromycin, and azithromycin in plasma by high-performance liquid chromatography with amperometric detection

Taninaka C., Ohtani H., Hanada E., Kotaki H., Sato H., Iga T.

Journal of Chromatography B: Biomedical Sciences and Applications （Journal of Chromatography B: Biomedical Sciences and Applications） 738 （ 2 ） 405 - 411 2000年02月

ISSN 13872273

In this study, a high-performance liquid chromatographic method was developed for the quantitative determination of erythromycin (EM), roxithromycin (RXM), and azithromycin (AZM) in rat plasma with amperometric detection under a standardized common condition using clarithromycin (CAM) as an internal standard. This method was also proved to be applicable for the determination of CAM by employing RXM as an internal standard. Each drug was extracted from 150 μl of plasma sample spiked with internal standard under an alkaline condition with tert.-butyl methyl ether. The detector cell potential for the oxidation of the drugs was set at +950 mV. The linearity of the calibration curves were preserved over the concentration ranges of 0.1-10 μg/ml for EM and RXM, and 0.03-3.0 μg/ml for CAM and AZM. Coefficients of variation and relative error were less than 9% and ±7%, respectively. The analytical method presented here was proved to be useful for the investigation of the pharmacokinetic characteristics of EM, CAM, RXM, and AZM in rats. (C) 2000 Elsevier Science B.V.

Access to Document (DOI)

Influence of extracellular K<sup>+</sup> concentrations on quinidine-induced K<sup>+</sup> current inhibition in rat ventricular myocytes

Hirota M., Ohtani H., Hanada E., Sato H., Kotaki H., Uemura H., Nakaya H., Tatsuji I.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 52 （ 1 ） 99 - 105 2000年01月

ISSN 00223573

Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+](o)) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (I(K)), the transient outward current (I(to)), and the inward rectifier potassium current (I(K1)), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on I(K), I(to), and I(K1) were evaluated under both normal ([K+](o) = 5.4 mM) and hypokalaemic ([K+](o) = 3.5 mM) conditions. In contrast to both I(K) and I(to), which were barely influenced by changes in [K+](o), I(K1) was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both I(K) and I(to) in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+](o). The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 μM (I(K)), and 17.6 and 17.3 μM (I(to)). Although higher concentrations of quinidine were required to inhibit I(K1), the inhibitory potency of quinidine was also found to be insensitive to changes in [K+](o). Thus, in rats, the inhibitory potency of quinidine for the K+ current-types I(K), I(to) and I(K1) is barely influenced by changes in [K+](o). These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalemia does not affect I(K) or I(to), it can inhibit I(K1) and can result in QT prolongation in-vivo.

Access to Document (DOI)

Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats

Ohtani H., Taninaka C., Hanada E., Kotaki H., Sato H., Sawada Y., Iga T.

Antimicrobial Agents and Chemotherapy （Antimicrobial Agents and Chemotherapy） 44 （ 10 ） 2630 - 2637 2000年

ISSN 00664804

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drag concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms · ml/μg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for malting a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Access to Document (DOI)

Effect of furanocoumarin derivatives in grapefruit juice on the uptake of vinblastine by Caco-2 cells and on the activity of cytochrome P450 3A4

Ohnishi A., Matsuo H., Yamada S., Takanaga H., Morimoto S., Shoyama Y., Ohtani H., Sawada Y.

British Journal of Pharmacology （British Journal of Pharmacology） 130 （ 6 ） 1369 - 1377 2000年

ISSN 00071188

1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [3H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [3H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [3H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is different from that of CYP3A4. 4. Further separation of the 60% methanol eluate afforded dihydroxybergamottin (DHBG). Both ethyl acetate extract of GFJ and DHBG increased steady-state [3H]-VBL uptake by LLC-GA5-COL300 cells. Besides DHBG, other furanocoumarins contained in GFJ, such as bergamottin, FC726, bergaptol and bergapten, increased the steady-state uptake of [3H]-VBL by Caco-2 cells. 5. The order of inhibitory potency of these compounds was FC726 > DHBG > bergamottin > bergapten > bergaptol. While, the IC50 values for inhibition of CYP3A4 were 0.075, 0.45, 1.0, 1.0 and > 20 μM, respectively. Bergaptol specifically inhibited VBL efflux. 6. DHBG was thus identified as a candidate for inhibitors of VBL transport, together with other furanocoumarins. Moreover, partly involvement of the P-gp inhibition was suggested. 7. Therefore, the inhibition of efflux transport of drugs as well as of drug metabolism by CYP3A4 could be an important cause of drug-GFJ interaction.

Access to Document (DOI)

Comparison of blood-brain barrier permeability in mice and rats using in situ brain perfusion technique

Murakami H., Takanaga H., Matsuo H., Ohtani H., Sawada Y.

American Journal of Physiology - Heart and Circulatory Physiology （American Journal of Physiology - Heart and Circulatory Physiology） 279 （ 3 48-3 ） H1022 - 8 2000年

ISSN 03636135

Here we present a method for measuring the permeability coefficient-surface area product (PS) values at the blood-brain barrier in mice, using the in situ brain perfusion technique originally developed for rats by Takasato et al. (Am J Physiol Heart Circ Physiol 247: H484-H493, 1984). Retrograde infusion into the right external carotid artery increased the carotid perfusion pressure in proportion to the perfusion rate. Intravascular volume and cerebral perfusion fluid flow at a perfusion rate of 1.0 ml/min in mice were similar to those in rats. In addition, the contribution of systemic blood to total flow in the hemisphere was small (only 3.2%). These findings indicated that this perfusion rate is suitable for mice. The PS values of more than 20 different compounds were determined in mice by using the in situ brain perfusion technique, and comparisons were made with data from rats. There was a close relationship (1:1) between the PS values in mice and rats, indicating that brain capillary permeabilities are similar in mice and rats.

Access to Document (DOI)

Efficient introduction of macromolecules and oligonucleotides into brain capillary endothelial cells using HVJ-liposomes.

Matsuo H, Okamura T, Chen J, Takanaga H, Ohtani H, Kaneda Y, Naito M, Tsuruo T, Sawada Y

Journal of drug targeting 8 （ 4 ） 207 - 16 2000年

ISSN 1061-186X

Access to Document (DOI)

Pharmacokinetic/pharmacodynamic analysis of tacrolimus-induced QT prolongation in guinea pigs

Minematsu T., Ohtani H., Sato H., Iga T.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 22 （ 12 ） 1341 - 1346 1999年12月

ISSN 09186158

Recently, several reports of clinical cases of QT prolongation and torsades de pointes, associated with the use of tacrolimus (FK506), have come to light. We have previously demonstrated FK506-induced QT prolongation in guinea pigs [Minematsu T., et al., Life Sci., 65, PL197-PL202 (1999)]. We now examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs, in order to evaluate the arrhythmogenicity of FK506 when compared with that of quinidine sulfate (QND). Thus, dose-response relationships for FK506 (0.01 or 0.1 mg/h/kg) or QND (30 mg/h/kg) were investigated during and after intravenous infusion and also following intravenous bolus administration of FK506 (0.2 mg/kg). The dose-response relationship between plasma drug concentration and QTc prolongation for FK506 and QND were subsequently analyzed using an effect compartment model. The pharmacodynamic parameters thus obtained were as follows: k(E0) 2.72 X 10-4 (min-1), E(max) 27.1 (ms), EC50 0.376 (ng/ml) for FK506; and k(E0) 0.148 (min-1), K 8.41 (ms · ml/μg) for QND. The anti-clockwise hysteresis observed for FK506-induced QT prolongation was successfully analyzed by the present pharmacokinetic/pharmacodynamic model, which may provide a rational basis for developing a clinical dosing regimen to avoid possible QT prolongation induced by FK506.

Access to Document (DOI)

Inhibitory effects of the antihistamines epinastine, terfenadine, and ebastine on potassium currents in rat ventricular myocytes

Ohtani H., Hanada E., Hirota M., Sato H., Kotaki H., Sawada Y., Uemura H., Nakaya H., Iga T.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 51 （ 9 ） 1059 - 1063 1999年09月

ISSN 00223573

We examined and compared the inhibitory effects of three non-sedating antihistamines, terfenadine, ebastine, and epinastine, on delayed rectifier potassium current (I(K)) and transient outward potassium current (I(to)) of rat isolated ventricular myocytes, using a patch clamp technique. Terfenadine, ebastine and epinastine were found to inhibit I(K) with IC50 values of 5.96, 15.3 and 145 μM, respectively. I(to) was suppressed by epinastine with an IC50 value of 69.5 μM. The order of arrhythmogenicity, assessed by the inhibition of I(K), was ranked as terfenadine > ebastine > epinastine, consistent with that of the potencies of each drug for QT prolongation reported in rats.

Access to Document (DOI)

Sustained QT prolongation induced by tacrolimus in guinea pigs

Minematsu T., Ohtani H., Sato H., Iga T.

Life Sciences （Life Sciences） 65 （ 14 ） 1999年08月

ISSN 00243205

Recently, clinical cases have been reported of QT prolongation and torsades de pointes associated with the use of tacrolimus (FK506). We examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs in order to evaluate the arrhythmogenicity of FK506 in comparison with quinidine (QND). FK506 (0.1 or 0.01 mg/hr/kg) or QND (30 mg/hr/kg) was intravenously infused to guinea pigs and time profiles of drug concentration in blood and QTc interval were examined during and after infusion. Both FK506 and QND evoked a significant QTc prolongation, and the dose-response relationship showed an anti-clockwise hysteresis, FK506-induced QTc prolongation persisted throughout the duration of the experiment despite a decline in the plasma FK506 concentration, whilst QND-induced QTc prolongation disappeared as plasma concentrations decreased. FK506 induced a sustained QTc prolongation in guinea pigs at drug concentrations in blood that correspond to its therapeutic range in human, suggesting that it might be of clinical significance to monitor the electrocardiogram, especially when patients have congenital or acquired QT-prolonging risk factors.

Access to Document (DOI)

Pharmacokinetic - pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats

Ohtani H., Sato H., Iga T., Kotaki H., Sawada Y.

Biopharmaceutics and Drug Disposition （Biopharmaceutics and Drug Disposition） 20 （ 2 ） 101 - 106 1999年02月

ISSN 01422782

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, E(max) and EC10 (ms) (where 10 ms of QT prolongation was evoked) of 0.73 μg/ml, 12.5 ms and 2.90 μg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

Access to Document (DOI)

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Hanada E., Ohtani H., Kotaki H., Sawada Y., Sato H., Iga T.

Journal of Pharmaceutical Sciences （Journal of Pharmaceutical Sciences） 88 （ 2 ） 234 - 240 1999年02月

ISSN 00223549

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhythmogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP-induced QT prolongation was proportional to its plasma concentration. In the case of EM, the E(max) model with an 'effect compartment' could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation)induced by coadministration of DP and EM in rats.

Access to Document (DOI)

Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats

Hirota M., Ohtani H., Hanada E., Kotaki H., Sawada Y., Iga T.

Life Sciences （Life Sciences） 62 （ 24 ） 2159 - 2169 1998年05月

ISSN 00243205

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 μg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 ± 1.40 vs 56.60 ± 0.748 msec, mean ± SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

Access to Document (DOI)

Determination of erythromycin concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection

Hanada E., Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Chromatography B: Biomedical Applications （Journal of Chromatography B: Biomedical Applications） 692 （ 2 ） 478 - 482 1997年05月

ISSN 15726495

A simple method for the quantitative determination of erythromycin (EM) concentrations in rat plasma and liver by high-performance liquid chromatography with amperometric detection was developed. EM was extracted from 200 μl of plasma or liver homogenate sample under sodium hydroxide alkaline conditions with tert.-butyl methyl ether. Oleandomycin was used as an internal standard. The recovery rate of EM was up to 100%. The detector cell potential for the oxidation of EM was +1100 mV. The calibration curves were linear over the concentration ranges 0.1-20.0 μg/ml for plasma and 0.5-100.0 μg/g for liver. The method was applied to the determination of the plasma and liver concentrations of EM in rats after intravenous administration (50 mg/kg dose). The method presented here has proved to be of great use for the investigation of the pharmacokinetic characteristics of EM in small animals such as rats.

Access to Document (DOI)

A comparative pharmacokinetic-pharmacodynamic study of the electrocardiographic effects of epinastine and terfenadine in rats

Ohtani H., Kotaki H., Sawada Y., Iga T.

Journal of Pharmacy and Pharmacology （Journal of Pharmacy and Pharmacology） 49 （ 4 ） 458 - 462 1997年04月

ISSN 00223573

The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg-1 h-1) or terfenadine (5, 10 or 15 mg kg-1 h-1) was intravenously infused into rats anaesthetized with methane and α-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner; its EC50 value was 792-1039 ng mL-1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100-200 ng mL-1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL-1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.

Access to Document (DOI)

Pharmacokinetic-pharmacodynamic analysis of the electrocardiographic effects of terfenadine and quinidine in rats

Ohtani H., Hanada E., Yamamoto K., Sawada Y., Iga T.

Biological and Pharmaceutical Bulletin （Biological and Pharmaceutical Bulletin） 19 （ 9 ） 1189 - 1196 1996年09月

ISSN 09186158

In establishing a method of electrocardiographic (ECG) measurement for investigating drug-induced ECG changes, we examined the ECG effects and pharmacokinetics of terfenadine (TFN) and quinidine (QND) in rats. The time profiles of the plasma concentration and ECG parameters, such as the QT interval determined from limb lead II (QT-II) and the precordial chest lead (QT-V), heart rate and PR interval, were examined during constant intravenous infusion of TFN (5 or 15 mg/kg/h) or QND sulfate dihydrate (10 or 30 mg/kg/h). Both agents provided significant and concentration-dependent QT prolongation. The plasma concentrations (C10), where 10 ms of QT prolongation was observed, were 1.03 μM for TFN and 5.12 μM for QND, respectively. The calculated plasma unbound concentration of C10 (C(10·f)) was 10.3 nM for TFN and 3.82 μM for QND, which coincides with previously reported in vitro values of IC50 for potassium channels. The drug-induced QT prolongation was quantitatively reproduced in rats within the clinical concentration range. The usefulness of our methodology for the evaluation of arrhythmogenic hazards of the drugs was also demonstrated.

Access to Document (DOI)

　前のページ - 次のページ　

大谷 壽一

論文 - 大谷 壽一

大谷　壽一

論文 - 大谷　壽一