• YAKHAK HOEJI
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• v.26 no.2
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• pp.105-110
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• 1982

The antihypertensive effect of clonidine administered concurrently with labetalol or metoprolol were studied with spontaneously hypertensive rats (SHR). The changes of heart rate were also observed in the same rats. Every drug was orally administered single dose after prechecking the systolic blood pressure and heart rate of SHR. The blood pressure of SHR in concurrently administered group was more significantly decreased than in alone administered group. The effective and stable decrease of blood pressure was maintained at the group of clonidine with labetalol (0.05+50mg/kg) for 9 hours. The group of clonidine with metoprolol (0.05+100mg/kg) manifested more marked decrease of blood pressure than the group of metoprolol (100mg/kg) alone for 9 hours. The diminishing effect of heart rate was enhanced in group of administering clonidine with labetalol, decreasing the dose of labetalol from 50mg/kg via 25mg/kg to 12.5mg/kg. On the other hand, in the group that clonidine was administered concurrently with metoprolol, the diminishing effect of heart rate was decreased with decreasing doses of metoprolol from 100mg/kg via 50mg/kg to 25mg/kg.

• YAKHAK HOEJI
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• v.28 no.5
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• pp.265-273
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• 1984

The effects of cinnarizine, $Ca^{2+}-antagonist$, on the antihypertensive effect of coadministered ${\beta}-blockers$, propranolol and metoprolol, were investigated in SHR. Drugs were coadministered orally for 4 weeks. Hemodynamic and biochemical changes induced by above drugs were determined to elucidate their mechanism of action. a) Cardiohypertropy of SHR was significantly improved by the treatment of ${\beta}-blockers$ as well as combination with cinnarizine and ${\beta}-blockers$. b) $Mg^{2+}-contents$ were increased in ventricle and decreased in plasma and aorta in all of the groups, especially in the group of propranolol with cinnarizine. c) c-GMP contents in ventricle were increased when cinnarizine was coadministered with propranolol, and c-GMP contents in aorta were increased when cinnarizine was coadministered with metoprolol, camparing with propranolol or metoprolol alone-treated group. d) Plasma renin activity appeared to be increased in cinnarizine treated alone, but reduced by combination with ${\beta}-blockers$. e) Triglycerides and $Na^+$ contents in serum were decreased in the group of metoprolol with cinnarizine, comparing with metoprolol alone-treated group. Increased $K^+\;and\;Ca^{2+}$excretions in urine by ${\beta}-blockers$ were inhibited by cinnarizine, so $Na^+/K^+$ excretion ratios were increased. Diuretic effects was showed in metoprolol alone treated group, but reduced when coadministered with cinnarizine.

• YAKHAK HOEJI
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• v.28 no.5
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• pp.249-256
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• 1984

The effects of $Ca^{2+}-antagonist$, cinnarizine, on the antihypertensive effects of propranolol and metoprolol were investigated in normal cat (i. v.) and SHR (p. o.). Cinnarizine increased the antihypertensive effect of propranolol, but not of metoprolol. It inhibited the heart rate decreasing effects of propranolol and metoprolol slightly. It decreased the norepinephrine-induced blood pressure increasing effect and isoproterenol-induced blood pressure decreasing effect when coadministered with metoprolol orally for 4 weeks in SHRs.

• YAKHAK HOEJI
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• v.29 no.1
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• pp.11-17
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• 1985

The behavioral effects of propranolol (60mg/kg) and metoprolol (100mg/kg) each alone and coadministered orally with cinnarizine (100mg/kg) were investigated and compared with each of betablockers alone treated group in rodents. Propranolol showed depressive effects through locomotor activity, conditioned avoidance response, rota-rod test, traction test, and analgesic effect in mice. When combined with cinnarizine and propranolol, the behavioral depressive effect of propranolol was reduced comparing with propranolol alone treated group. However, metoprolol alone or combined with cinnarizine didn't showed any behavioral depressive effect so much as propranolol.

• Archives of Pharmacal Research
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• v.23 no.3
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• pp.230-236
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• 2000

(1'R, 2R)-, (1'R, 2S)-, (1'S, 2R)- and (1'S, 2S)-$\alpha$-hydroxymetoprolol; (2R)- and (2S)-O-des-methylmetoprolol; and (2R)- and (2S)-metoprolol acid are major metabolites of (2R)-and (2S)-metoprolol, $\beta$-adrenergic antagonist. The focus of most chiral separation methods until now has been on determination of the enantiomeric parent drug. However, it is just as important to be able to follow the metabolism of the enantiomers and their possible chiral metabolites. Therefore, for the study of stereoselective metabolism and pharmacokinetics of metoprolol, the chiral separation of the enantiomers of metoprolol and its metabolites has been investigated using four chiral stationary phases, i.e., Chiralcel OD, Chiral-AGP, Cyclobond I and Sumichiral OA-4900 columns. Metoprolol acid was resolved only by Sumichiral OA-4900. Chiralcel OD provided the highest separation factor and resolution value for metoprolol and O-desmethylmetoprolol and partially resolved the four stereoisomers of $\alpha$-hydroxymetoprolol. Diastereomeric $\alpha$-hydroxymetoprolols were resolved using the coupled column chromatographic system of two chiral stationary phases, Sumichiral OA-4900 column and Chiralcel OD column.

• YAKHAK HOEJI
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• v.28 no.5
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• pp.257-263
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• 1984

In our former report we observed that cinnarizine influenced the antihypertensive effect of propranolol beneficially, but not of metoprolol in SHR and normal cat. Cardiac contractilities and smooth muscle relaxations induced by above drugs were measured to elucidate their mechanism of action. In cinnarizine and propranolol treated group, both of negative inotropic and ${\beta}-blocking$ activity of propranolol in perfused rat hearts were increased and propranolol induced contraction in isolated arterial and trachea smooth muscle of the guinea pig was antagonized comparing to propranolol alone treated group. However, in the cinnarizine and metoprolol treated group, no significant differences in activity on the above were observed compared to metoprolol alone treated group.

• Archives of Pharmacal Research
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• v.22 no.6
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• pp.614-618
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• 1999

A reversed-phase high-performace liquid chromatographic method was developed to determine the optical purity of metoprolol enantiomers. The enantiomers were converted to diastereomeric derivatives using (-)-menthyl chloroformate reagent. Separation of the enantiomers as diastereomers was achieved by reversed-phase HPLC within 30 min using Inertsil C8 column. This method allowed determination of 0.05% of either enantiomer in the presence of its stereoisomer and method validation showed adequate linearity over the required range. Owing to the reaction condition during the derivatization with (-)-menthyl chloroformate, the possibility of racemization had to be established. Different ratios of (S)-(-)-metoprolol and (R)-(+)-metoprolol were prepared. Enantiomeric separation of these mixtures took place on a chiralcel OD column or, after derivatization with (-)-menthyl chloroformate, on a C8 column. The results form the these two independent separation systems were compared with trace racemization and were in very good agreement. No racemization was found during the experiment.

• Archives of Pharmacal Research
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• v.23 no.3
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• pp.226-229
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• 2000

To obtain the standard compounds of metoprolol for a pharmacokinetic study, a convenient synthetic procedure to prepare enantiomers of metoprolol (3a) and its major metaboites, 2-4-(2-hydroxy-3-isopropylamino)propoxyphenylathanol (3b) and 4-(2-hydroxy-3- isopropylamino) pro-poxyphenylacetic acid (4), was developed from their respective starting materials, 4-(2-methoxyethyl)phenol (1a), 4-(2-hydroxyethyl)phenol (1b) and methyl 4-hydroxyphenylacetate (1c). These phenolic compounds (1a, b, c) were converted in situ to their corresponding phenoxides with sodium hydroxide treatment followed by (R)- or (S)-epichlorohydrin treatment. The resulting epoxides 2 were transformed to 3 through reaction with isopropylamine. Ester 3c was hydrolyzed to the metabolite 4. Measured using the HPLC method on chiral column without any derivatization, the optical purity of enantiomers of metoprolol and o-demethylated metabolite 3b ranged between 96-99 ％ ee and that of enantiomers of carboxylic acid metabolite 4 ranged 91％ ee.

• The Korean Journal of Pharmacology
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• v.31 no.2
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• pp.251-259
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• 1995

Pharmacokinetics and pharmacodynamics of metoprolol, a selective beta-l blocker, were examined for 360 minutes after intravenous bolus administration of metoprolol to 6 dogs. Plasma concentration and excreted amount in the urine metoprolol were measured by liquid chromatography with fluorescence detection. PR interval and heart rate were measured by ECG monitoring. Blood pressure was monitored through intraarterial catheter in femoral artery and cardiac output by thermodilution method using Swan-Ganz catheter. To analyze the effect site concentration-response relationship, plasma concentration and pharmacological effects were simultaneously fitted to a two pharmacokinetic compartment linked to pharmacodynamic model with NONLIN program. Results are as follows. 1) The plasma concentration of metoprolol after intrvenous injection decreased biexponentially. The terminal half-life estimated was $1.33{\pm}0.40$ hours and the volume of distribution at steady state (Vdss) and the total body clearance were $1.04{\pm}0.4\;L/kg,\;6.55{\pm}2.21\;L/hr$, respectively. The central compartment volume of distribution and peripheral compartment volume of distribution were $0.35{\pm}0.14L/kg\;and\;0.69{\pm}0.34L/kg$. The renal clearance and intercompartment clearance were $0.53{\pm}0.25\;L/min\;and\;0.35{\pm}0.19\;L/min$. 2) Simulated biophase concentration-response curve shows hyperbolic relationship and the estimated concentration-effect relationship was best explained by Emax model when the prolongation of PR interval and the reduction of the heart rate were used as pharmacodynamic parameters. Emax and EC50 were estimated to be $26.3{\pm}4.7\;msec\;and\;88.8{\pm}82.3\;g/ml$ for PR interval, and $48.7{\pm}18.8\;beats/min\;and\;113.5{\pm}78.7\;ng/ml$ for heart rate, respectively. 3) The changes of cardiac output-effect site concentration relationship was best fitted by a linear model and the slope of the relationship was $0.005{\pm}0.003$. Diastolic blood pressure-effect site concentration relationship was also explained by the linear model and the slope of the relationship was $0.038{\pm}0.034$.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.356.3-357
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• 2002

Metoprolol (MT) is one kinds of adrenergic beta-blockers. Its (S)-enantiomer is known to be more active than the (R). Recently. the x-ray structure of beta-blocker. (S)-propranolol (a-naphthyl analogue), complexed in a mould fungal cellulase. Cel7A. was reported and the (R)-form did not build any complex. And in our previous study the conformation and stability of MT in carboxymethylated beta-cyclodextrin (BCD) complex was determined by NMR. HPLC, UV and electrophoresis measurement. (omitted)