• Archives of Pharmacal Research
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• 제25권4호
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• pp.541-545
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• 2002

Pharmacokinetic characteristics of Acebutolol and its main metabolite, diacetolol, following a single 10 mg/kg oral dose, were investigated in rabbits with carbon tetrachloride-induced hepatic failure. Plasma concentrations of acebutolol and diacetolol were determined by a high performance liquid chromatography assay. The area under the plasma concentration-time curves (AUC) and maximum plasma concentration ($C_{max}$) of acebutolol were significantly increased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. The ratio of the diacetolol to total acebutolol in plasma (i.e., metabolite percentage rate) was significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Volume of distribution ($V_{d}$) and total body clearance ($CL_{t}$) of acebutolol were significantly decreased in moderate and severe carbon tetrachloride-induced hepatic failure rabbits. Slope of terminal phase ($\beta$) of acebutolol was significantly decreased in hepatic failure rabbits. These findings suggest that the $V_{d},{\;}CL_{t}$ and $\beta$ of acebutolol were significantly decreased as a result of inhibition of the hepatic metabolism in moderate to severe hepatic failure rabbits. Therefore, dose adjustment may be necessary for acebutolol in hypertensive patients with hepatic damage.

• Journal of Pharmaceutical Investigation
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• 제38권3호
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• pp.151-155
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• 2008

Circadian variations of acebutolol and its main metabolite, diacetolol pharmacokinetics were studied after a single oral administration of acebutolol (10 mg/kg) to eight rabbits at 10 : 00 AM (in the morning) and 10 : 00 PM (at night). The plasma concentration profiles of acebutolol were significantly different (P<0.05) between 10 : 00 AM and 22 : 00 PM, suggesting circadian variations of pharmacokinetic behaviors. A significant circadian rhythm of pharmacokinetic parameters was noted in rabbits, showing higher total body clearance (CL/F), and lower the area under the plasma concentration-time curves (AUC) of acebutolol than that at night. The half-life ($t_{1/2}$) of acebutolol and diacetolol were also significantly shorter in the morning than at night (P<0.05). Metabolite-parent AUC ratio at night significantly decreased compared to in the morning, implying that night time could inhibit acebutolol metabolism than in the morning. From this study there was an administration-time difference of acebutolol pharmacokinetics in the rabbits. The optimized dosing regimen of acebutolol can be decided by considering circadian rhythm so that the effective therapies are established for patients.

• 한국임상약학회지
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• 제11권2호
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• pp.57-61
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• 2001

The effect of circadian rhythm on the pharmacokinetics of acebutolol was studied in rabbits administered intravenous 5 mg/kg dose of acebutolol at 09:00 in the morning (a.m) and 22:00 in the evening (p.m). A significant effect of circadian rhythm of pbarmacokinetic parameters as a function of time of day was noted in rabbits, showing lower total body clearance (CLt), higher plasma concentration and the area under the plasma concentration time curve (AUC) when acebutolol was given in the evening. The plasma concentration of acebutolol was increased significantly (p<0.05) at 12-24 hr after dosing in the evening. The AUC was greater in the evening $(111\%)$ than that in the morning and $CL_t$, was higher when acebutolol was given in the morning ($1.12\pm0.24$ ml/hr) versus in the evening ($1.01\pm0.22$ ml/hr), but those were not significant. Therefore, It is reasonable to consider individual circadian rhythm for effective dosage regimen of acebutolol in clinical chronotherapeutics.

• Journal of Pharmaceutical Investigation
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• 제23권3호
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• pp.133-137
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• 1993

A high-performance liquid chromatographic assay using ion-pair reverse-phase system was developed for the separation of acebutolol and acebutolol acetyl metabolite in plasma. A ion-pair reversephase system consisting of an ODS-bonded silica column and a mixture of 20% $CH_3CN$, 0.1% $H_3PO_4$, 0.035 M heptanesulfonic acid and 0.005 M tetrabutylammonium hydrogen sulfate as the mobile phase were used. Triamterene was employed as an internal standard. Based on 0.2 ml of plasma, the detection limits were 10.4 ng/ml for acebutolol and 10.3 ng/ml of acebutolol acetyl metabolite at the signal-to-noise ratio of 3:1.

• 약학회지
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• 제45권6호
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• pp.664-669
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• 2001

Acebutolol is almost absorbed after oral administration, but its bioavailability is reduced because of considerable first-pass metabolism through the gastrointestinal tract and liver. The purpose of this study was to report the pharmacokinetic changes of acebutolol (15 mg/kg,oral) and its main metabolite, diacetolol in rabbits pretreated (15 mg/kg, oral) and coadministered (15 mg/kg, S. C., bid for 3 days) with diltiazem. The plasma concentration and area under the plasma concentration-time curves (AUC) of acebutolol and diacetolol were significantly increased in rabbits pretreated and coadministered with diltazem. The elimination rate constant ( $K_{el}$ ) and total body clearances (CL $_{t}$) of acebutolol and diacetolol were significantly decreased and half-life of those were significantly prolonged in the rabbit. Metabolite percentage rate of diacetolol to the plasma concentration of total acebutolol in rabbits pretreated and coadministered with diltiazem were significantly decreased. The results suggest that the dosage of acebutolol should be adjusted when the drug would be administered chronically with diltiazem in a clinical situation.n.

• Archives of Pharmacal Research
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• 제26권6호
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• pp.499-503
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• 2003

Because physiological changes that potentially alter pharmacokinetics occurs in diabetes mellitus patients, pharamacokinetics of drugs used in the treatment of hypertension was studied using acebutolol as a model anti-hypertensive drug. Thus, the pharmacokinetics of acebutolol was investigated after oral administration of acebutolol (15 mg/kg) to control rabbits and rabbits with acute or chronic diabetes mellitus induced by alloxan. Kidney and liver functions were documented for acute and chronic diabetes mellitus groups based on plasma chemistry data. After oral administration of acebutolol to acute and chronic groups, the plasma concentrations appeared higher; As a result, area under the plasma concentration-time curve from time zero to time infinity10575 and 8668 $\mu g\cdot$ h/mL for acute and chronic group, respectively. In comparison, the area was apparently smaller in the control group (i.e., 7132 $\mu g\cdot$ h/mL). The half-life in acute groups was significantly prolonged 8.45 h compared with the half-life in the control group (i.e., 6.30 h). Alteration in acebutolol pharmacokinetics was more pronounced in the acute group as evidenced by the significantly higher values the area under the plasma concentration time curve, absorption rate constant and maximum plasma concentration compared with chronic or control group. Therefore, these observations indicate that acebutolol pharmacokinetics may be affected in patients with diabetes mellitus, especially in the early stage of the disease.

• 대한약리학회지
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• 제23권1호
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• pp.9-14
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• 1987

Adrenergic beta 1 수용체 봉쇄 약물인 acebutolol과 항 경련제로 사용되고 있는 carbamazepine은 실험적으로 ouabain유발 부정맥을 정상 심박동으로 환원시키는데 유효하다고 보고되었으나 그 상호 작용에 대해서는 밝혀진 바가 없다. 이에 본 실험에서는 가토에 ouabain 투여로 부정맥을 유발시킨 후 acebutolol과 carbamazepine을 단독 혹은 병용 투여하여 이 두 약물이 ouabain 유발 부정맥에 미치는 영향과 그 상호 작용을 규명하고자 하였다. 실험 결과 ouabain 유발 부정맥은 acebutolol 혹은 carbamazepine 단독 투여로 정상 심박동으로 환원되었으며 용량이 감소함에 따라 정상 심박동으로 회복하는데 요하는 시간이 연장되었다. 또 단독 투여시 항 부정맥 효과를 볼 수 없었던 용량을 병용 투여하였을 때 ouabain 유발 부정맥은 즉시 정상 심박동으로 환원되었으며 상기 용량의 두 약물을 병용하여 전처치함으로써 ouabain의 부정맥 유발 용량이 의의있게 증가되었다(P<0.01). 이상의 결과로 acebutolol과 carbamazepine은 ouabain 유발 부정맥을 용량 의존적으로 억제시키며 상협적인 상호작용(synergistic interaction)을 나타낸다고 사료된다.

• Journal of Pharmaceutical Investigation
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• 제31권3호
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• pp.161-165
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• 2001

Acebutolol (ABT) is almost absorbed after oral administration, but its bioavailability is reduced because of considerable first-pass metabolism in the gastrointestine and liver. The purpose of this study was to report the pharmacokinetic changes of ABT and its metabolite, diacetolol (DAT) after oral administration of acebutolol to control rabbits and rabbits with mild and severe folate-induced renal failure (FIRRs). Both of the area under the plasma concentration-time curve $(AUC^0_{\infty})$ of ABT and DAT were significantly increased in mild (p<0.05) and severe FIRRs (p<0.01), but the $AUC^0_{\infty}$ of DAT was more influenced than that of ABT in severe rabbits. There was a good correlation between serum creatinine and both of $AUC^0_{\infty}$ of ABT and DAT. The elimination half-life of ABT and DAT was significantly prolonged in mild (p<0.05) and severe (p<0.01) FIRRs, but the half-life of DAT was more influenced than that of ABT in severe FIRRs. The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal disorder on the base of the serum creatinine concentration.

• Biomolecules & Therapeutics
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• 제26권5호
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• pp.458-463
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• 2018

The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.

• 대한약학회:학술대회논문집
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• 대한약학회 2001년도 Proceedings of International Convention of the Pharmaceutical Society of Korea
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• pp.310.1-310.1
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• 2001