• Archives of Pharmacal Research
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• 제29권1호
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• pp.102-107
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• 2006

The aim of present study is to investigate the effect of naringin on the pharmacokinetics of verapamil and its major metabolite, norverapamil in rabbits. The pharmacokinetic parameters of verapamil and norverapamil were determined after administering verapamil (9 mg/kg) orally to rabbits in the pretreated with naringin (1.5, 7.5, and 15 mg/kg). Naringin pretreatment significantly altered the pharmacokinetic parameters of verapamil. Compared with the control group (given verapamil alone), the $K_a,\;C_{max}$ and AUC of verapamil were significantly (p<0.05 or p<0.01) increased in the pretreatment of naringin, However there were no significant change in $T_{max}\;and\;t_{1/2}$ of verapamil. Consequently, pretreatment of naringin significantly (p<0.05, p<0.01) increased the AB% of verapamil significantly in a dose dependent manner (p<0.05 or p<0.01 ), and elevated the RB% of verapamil by 1.26- to 1.69-fold. the MR of verapamil were significantly (p<0.05) increased in the pretreatment of naringin, implying that pretreatment of naringin may effectively inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of naringin enhanced the oral bioavailability of verapamil. Based on these results, the verapamil dosage should be adjusted when given with naringin or a naringin-containing dietary supplement.

• 약학회지
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• 제49권5호
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• pp.380-385
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• 2005

The aim of this study is to investigate the effects of verapamil on the pharmacokinetics of tamoxifen following oral administration of tamoxifen with verapamil to rats. Tamoxifen (10 mg/kg) was administered orally in the presence or absence of verapamil (1, 3 or 6 mg/kg). Compared to the control group (given tamoxifen alone), the presence of verapamil significantly (p<0.05 by 1 mg/kg, p<0.01 by 3 and 6 mg/kg) increased the areas under the plasma concentration-time curve (AUC) and the peak concentrations ($C_{max}$) of tamoxifen. Consequently, the relative bioavailability ($RB\%$) of tamoxifen with verapamil was 1.6-2.1 fold higher than that of the control. But the time to reach peak concentration ($T_{max}$) and the terminal half-life ($t_{1/2}$) of tamoxifen were not altered significantly in the presence of verapamil. The increased AUC and $C_{max}$ of tamox­ifen in the presence of verapamil might be associated with the inhibition by verapamil of the P-glycoprotein and the first­pass metabolizing enzyme CYP3A4 in small intestinal mucosa. The drug interaction should be taken into consideration when tamoxifen is used to the patient with verapamil in the clinical setting.

• 한국임상약학회지
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• 제18권1호
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• pp.6-10
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• 2008

This study investigated the effect of long-term administration of pioglitazone on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats coadministered pioglitazone (0.5 mg/kg) or pretreated with pioglitazone (0.5 mg/kg) for 3 and 9 days. Compared to oral control group, the presence of pioglitazone significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC) of verapamil by 48.6% (coad), 61.1% (3 days) and 56.5% (9 days), and the peak concentration($C_{max}$) by 65.1% (coad), 76.8% (3 days) and 66.4% (9 days). The absolute bioavailability (AB%) of verapamil was significantly (p<0.05) higher by 6.2% (coad), 6.7% (3 days), 6.5% (9 days) compared to control (4.2%), and presence of pioglitazone was no significant change in the terminal half-life ($t_{1/2}$) and the time to reach the peak concentration($T_{max}$) of verapamil. Our results indicate that pioglitazone significantly enhanced oral bioavailability of verapamil in rats, implying that presence of pioglitazone could be effective to inhibit the CYP3A4-mediated metabolism of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with pioglitazone.

• Archives of Pharmacal Research
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• 제26권9호
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• pp.763-767
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• 2003

The differences in pharmacokinetic behavior and tissue distribution of verapamil and its enantiomers were investigated in rats. In high-performance liquid chromatographic method, an achiral ODS column (150 mm $\times$ 4.6 mm i.d.) with the mobile phase consisting of methanol-water (73:30, v/v) was used for the determination of the concentration for racemic verapamil, and a Chiralcel OJ column (250 mm$\times$4.6 mm i.d.) with the mixture of n-haxane-ethanol-triethylamine (85:15:0.2, v/v/v) as mobile phase was used to determine the concentrations of verapamil enantiomers. A fluorescence detector in the analytical system was set at excitation and emission wavelengths of 275 nm and 315 nm. The differences between enantiomers were apparent in the pharmacokinetics in rats. The area under the concentration-time curve (AUC) of S-(-) verapamil was higher than that of R-(+) verapamil. The half-distribution time ($T_{1/2(\alpha)}$) of S-(-) verapamil which distributing to tissue from blood was shorter than that of R-(+) verapamil, but the elimination half-time ($T_{1/2(\beta)}$) was longer in rat following oral administration of racemic verapamil. At 1.3 h after oral administration of racemic verapamil, however, there were no significant differences between enantiomers for the distributions in major tissues such as heart, cerebrum, cerebellum, liver, spleen and kidney.

• 약학회지
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• 제35권2호
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• pp.85-98
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• 1991

Verapamil, $Ca^{2+}$-channel blocker, when given into vein or into carotid artery, produced the decrease of urine flow accompanied with the decreased amounts of Na$^{+}$ and $K^{+}$ excreted in urine ($E_{Na}, E_{K}$) and with the decreased clearances of free water (C$_{H_2O}$) and osmolar substance (C$_{osm}$), and then increased reabsorption of Na$^{+}$ and $K^{+}$ in renal tubules (R$_{Na}$, R$_{N}$), glomeruler filtration rate (GFR) and renal plasma flow (RPF) were inhibited when verapamil was given into carotid artery, but were only tendency of reduction when given intravenously. Verapamil, when infused into a renal artery, exhibited diuresis accompanied with the increased GER, RPF, E$_{Na}$ and E$_{K}$, with the decreased filtration fraction (FF) in only infused kidney. At the same time, $C_{H_2O}$ was not changed, R$_{Na}$ and R$_{K}$ were reduced. Antidiuretic action by verapamil administered into vein or into carotid artery in normal kidney was reversed to diuretic action in denervated kidney. At this time, parameters of renal function exhibited the opposite phenomena compared to that elicited by verapamil in normal kidney, wherease renal denervation did not influence the action of verapamil infused into a renal artery. Above results suggest that verapamil produce both antidiuresis through nervous system centrally, not endogenous substances and diuresis by direct action in the kidney. Diurectic action are caused by hemodynamic improvement through dilatioon of vas efferense and by greatly inhibited reabsorption of electrolytes in distal tubules.

• Journal of Chest Surgery
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• 제19권2호
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• pp.217-224
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• 1986

Using an isolated rat heart preparation under both aerobic and ischemic condition, we observed the myocardial protective effect of verapamil cardioplegia. Isolated working hearts were subjected to global ischemia at 25oC. Before ischemic arrest, rat hearts were treated with cold potassium cardioplegic solution [K=30 mEq/L] in control group and cold potassium cardioplegic solution added with verapamil [1 mg/L] in other group. After 30 min. of ischemia, hemodynamic parameters and creatine kinase leakage in coronary effluent were observed. Verapamil group exhibited greater percent of recovery in aortic pressure [p<0.01], aortic flow [p<0.01], and stroke volume [p<0.05]. Although there were no significant difference in creatine kinase leakage and the percent recovery of cardiac output between verapamil and control group, verapamil group showed better myocardial function. But the time to recover regular sinus rhythm was significantly [p<0.001] prolonged in verapamil group.

• 대한수의학회지
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• 제28권1호
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• pp.29-36
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• 1988

To examine the selectivity of verapamil, used in the cardiovascular diseases, on alpha-1 and alpha-2 adrenoceptor-induced pressor rsponses, effects of verapamil on alpha-adrenoceptor agonist-induced pressor responses were investigated in urethane-anesthetized rabbits, spinal rabbits, rats and pithed rats. To evaluate the effects of verapamil on each pressor response induced by norepinephrine, phenylephrine and clonidine, these agonists were previously injected into a ear vein, and then same procedures were performed 1~2 min after treatment with intravenous verapamil. The results are summarized as follows: 1. Intravenous verapamil produced dose-dependent depressor response in rabbits and rats. 2. Pressor responses to intravenous norepinephrine($10{\mu}g/kg$) and phenylphrine($30{\mu}g/kg$) were inhibited by pretreatment with intravenous verapamil in rabbits and no difference was noted between the degree of both inhibitions of the pressor response by verapamil. 3. Pressor responses to intravenous norepinephrine($3{\mu}g/kg$), phenylephrine($20{\mu}g/kg$) and clonidine ($300{\mu}g/kg$) were inhibited by pretreatment with intravenous verapamil in spinal rabbits. No difference was noted between the inhibition of norepinephrine-induced pressor response and that of phenylephrine-induced pressor response by verapamil. The inhibition of clonidine-induced pressor response by verapamil was more prominent than that of norepinephrine- or phenylephrine-induced pressor response. 4. Pressor responses to intravenous norepinephrine($3{\mu}g/kg$) and phenylephrine($10{\mu}g/kg$) were inhibited by pretreatment with intravenous verapairlil in rats and no difference was noted between the degree of both inhibitions of the pressor response by verapamil. 5. Pressor responses to intravenous norepinephrine ($3{\mu}g/kg$), phenylephrine($30{\mu}g/kg$) and clonidine($100{\mu}g/kg$) were inhibited by pretreatment with intravenous verapamil in pithed rats. No difference was noted between the inhibition of norepinephrine-induced pressor response and that of phenylephrine-induced pressor response by verapamil. The inhibition of clonidine-induced pressor response by verapamil was more prominent than that of norepinephrine- or phenylephrine-induced pressor response. These results suggest that verapamil significantly inhibits both pressor responses mediated by alpha-1 and alpha-2 adrenoceptors and the inhibition is greater in alpha-2 adrenoceptor-induced response than in alpha-1 adrenoceptor-induced one, and calcium channel takes part in the process of the pressor response mediated by alpha-1 adrenoceptors as well as alpha-2 adrenoceptors.

• Journal of Pharmaceutical Investigation
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• 제34권1호
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• pp.15-21
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• 2004

The pharmacokinetics of orally administered verapamil (10 mg/kg) was studied in six rabbits after 20 min pretreatment with quercetin ad coadministration of quercetin (2.0 mg/kg, 1 mg/g and 20 mg/kg, respectively). Pretreatment with quercetin significantly (p < 0.01, p < 0.05) increased the plasma concentration of verapamil. However, coadministration of quercetin showed no significantly effect on the pharmacokinetic parameters of verapamil. The elimination rate constant $(K_{el})$ of verapamil pretreated with quercetin (1 mg/kg and 20 mg/kg) was significantly (p < 0.05) reduced compared with control. The area under the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of verapamil pretreated with quercetin (2.0 mg/kg, 10 mg/kg and 20 mg/kg) were increased significantly (p < 0.01, p < 0.05) compared with control. Pretreatment with quercetin (2.0 mg/kg, 10 mg/kg and 20 mg/kg) significantly (p < 0.01, p < 0.05) increased the relative bioavailability of verapamil to 159 - 219%. These results suggest that quercetin alters disposition of verapamil by inhibition of P-glycoprotein efflux pump and its first-pass metabolism. The dosage of verapamil should be adjusted when it is administered chronically with quercetin in a clinical situation.

• Biomolecules & Therapeutics
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• 제22권6호
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• pp.553-557
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• 2014

Verapamil is used in the treatment of hypertension, angina pectoris, and atrial fibrillation. Recently, several studies have demonstrated that verapamil increased the optic nerve head blood flow and improved the retrobulbar circulation. All these show that verapamil is potentially useful for ophthalmic treatment. Thus, the aim of this study is to investigate whether verapamil could protect human lens epithelial cell (HLEC) from oxidative stress induced by $H_2O_2$ and the cellular mechanism underlying this protective function. The viability of HLEC was determined by the MTT assay and apoptotic cell death was analyzed by Hoechst 33258 staining. Moreover, Caspase-3 expression was detected by immunocytochemistry and flow cytometry analysis. We also detected Caspase-3 mRNA expression by reverse-transcription-polymerase chain reaction and the GSH content in cell culture. The results showed that oxidative stress produced significant cell apoptotic death and it was reduced by previous treatment with the verapamil. Verapamil was effective in reducing HLEC death mainly through reducing the expression level of apoptosis-related proteins, caspase-3, and increasing glutathione content. Therefore, it was suggested that verapamil was effective in reducing HLEC apoptosis induced by $H_2O_2$.

• 대한핵의학회지
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• 제38권1호
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• pp.85-98
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• 2004

목적: 다약제내성(MDR) 극복제 verapamil은 MDR이 발현된 암세포에서 Tc-99m MIBI(MIBI)와 tetrofosmin(TF)의 섭취를 증가시키는 것으로 알려져 있으나, 세포의 종류에 따라서는 MIBI와 TF의 섭취를 감소시킬 수 있다는 보고가 있다. 본 연구는 암세포의 종류에 따라 verpamile이 MIBI와 TF의 섭취에 미치는 영향이 세포에 따른 차이가 있는지를 알아보고, 이러한 차이가 세포독성이나 PKC효소의 발현에 따른 차이인가를 알아보았다. 방법: 백혈병세포 K562세포와 유방암세포 MCF7, 난소암세포 SK-OV-3 세포 및 MDR이 유발된 K562(Adr)세포를 배양하였다. 시험관에서 $1{\times}10^6\;cells/ml$ 농도의 single-cell suspension 상태로 분주하고 verapamil을 1, 10, 50, 100, $200{\mu}M$의 농도로 처리한 후 MIBI와 TF를 배양한 후, $37^{\circ}C$에서 1, 15, 30, 45, 60분 동안 반응시킨 후 pellet과 supernatant의 방사능 치를 감마계수기로 측정하여 투여한 방사능 치에 대한 세포내 섭취백분율로 표시하였다. Verapamil의 세포독성은 MTT assay로 측정하였고, 세포내의 PKC isotypes의 변화는 western blotting analysis로 평가하였다. 결과: 4종류의 세포 모두에서 MIBI와 TF의 섭취는 1, 15, 30, 45, 60분 배양 시간에 따라 증가하였다. verapamil을 처리시 다약제 내성이 유발된 K562(Adr)세포에서 $100{\mu}M$의 농도까지는 MIBI와 TF 섭취가 증가하였고, 최대 $10{\mu}M$에서 10배 증가하였다. 그러나 K562세포를 verapamil $1{\mu}M$로 처리하였을 때는 기저치와 유사하였으나, verapamil의 농도가 증가함에 따라 MIBI와 TF의 세포섭취는 모두 감소하였다. K562세포의 60분 MIBI 섭취율은 79%($10{\mu}M$), 47%($50{\mu}M$), 29%($100{\mu}M$), 1.5%($200{\mu}M$)로 verapamil의 용량이 증가함에 따라 감소하였으며, TF 섭취율도 84% ($10{\mu}M$), 60%($50{\mu}M$), 42%($100{\mu}M$), 2.7%($200{\mu}M$)로 감소하였다. MCF7, SK-OV-3세포에서는 verapamil $10{\mu}M$까지는 MIBI와 TF의 섭취가 기저치와 유사하거나 소량 증가하였으나 $50{\mu}M$이상의 용량에서는 감소하여 $100{\mu}M$에서는 각각 40%와 5%만 섭취되었다. MTT assay상 K562(Adr)세포에서는 verapamil $100{\mu}M$ 이상에서는 유의하게 낮았으나 다른 세포는 $200{\mu}M$까지에도 차이가 없었다. PKC 아형의 분석상 PKC $\varepsilon$이 K562(Adr)세포에서 많이 발현되었으나, K562와 K562(Adr)세포에서는 verapamil처리에 따른 PKC 아형의 변화는 없었다. 결론: Verapamil은 암세포의 종류에 따라 MIBI와 TF의 섭취를 감소시켰고, 고용량에는 MDR세포의 섭취도 감소시켰으며 이러한 현상은 세포독성 이나 PKC효소 아형과는 관련이 없었다. 그러므로 MDR의 진단시 verapamil을 처치에 따른 MIBI와 TF의 섭취 정도를 기준으로 하는 경우에는, verapamil의 농도와 세포의 종류에 따라 현저한 차이가 있을 수 있다는 점을 생각하여야 한다.