Pharmacokinetic Parameters Of Verapamil Research Articles

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration–time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

Synergistic antifibrotic effect of verapamil and interferon-γ in rats: partially based on enhanced verapamil oral bioavailability

The objective of this study was to investigate the synergistic antifibrotic effect of verapamil and interferon-gamma (IFN-gamma) on rat liver fibrosis and its potential pharmacokinetic-based mechanism. Rat liver fibrosis model was successfully established, and both the therapeutic effects and pharmacokinetic parameters of verapamil were evaluated after the administration of verapamil with or without IFN-gamma. The activities of cytochrome P450 3A (CYP3A) and the expression of multidrug resistance (Mdr) mRNA were measured in liver and small intestine. The results showed the synergistic antifibrotic effect of verapamil and IFN-gamma in rat liver fibrosis, in terms of decreased serum L-alanine aminotransferase activity and liver hydroxyproline content and improved liver histopathology, when compared with rats treated with verapamil or IFN-gamma alone. Meanwhile, the area under the curve of verapamil increased significantly after single administration of verapamil and IFN-gamma and the concentration of verapamil in plasma increased, but the metabolite : parent ratio of verapamil decreased after consecutive administrations of verapamil and IFN-gamma. Furthermore, the activities of CYP3A in both the liver and the small intestine and the expression of Mdr in small intestine decreased in rats treated with verapamil and IFN-gamma. All these results indicated that the combination of verapamil and IFN-gamma exerts a synergistic antifibrotic effect on rat liver fibrosis. The mechanism was partially based on the enhanced oral bioavailability of verapamil by increasing the intestinal absorption as well as reducing the first-pass metabolism, through inhibition of CYP3A activity and P-glycoprotein expression by IFN-gamma

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg(-1)) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg(-1)). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the C(max) and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg(-1) quercetin. There was no significant change in T(max) and terminal plasma half-life (t(1/2)) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P < 0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.

Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin

Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil. The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared in 14 healthy male Korean volunteers (age range 22-28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 x 2 crossover model in random order. The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration-time curve (AUC (0-infinity)) and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The (AUC (0-infinity)) of norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite-parent ratio was significantly reduced (29.2%) in the presence of lovastatin. Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5-64.8%, and the peak plasma concentration (C(max)) of verapamil by 34.1-65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T(max)) and the terminal half-life (t(1/2)) of verapamil in the presence of lovastatin. The AUC and C(max) of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.

Effects of simvastatinon the pharmacokinetics of verapamil and its main metabolite, norverapamil, in rats

The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were determined after the oral administration of verapamil (9 mg/kg) in the presence or absence of simvastatin (0.3 and 1.0 mg/kg). The pharmacokinetics of verapamil were significantly altered by the coadministration of simvastatin compared with those in the control group (given verapamil alone). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of verapamil were significantly increased (P < 0.05 at 0.3 mg/kg; P < 0.01 at 1.0 mg/kg) by simvastatin. Consequently, the absolute bioavailability (A.B.) of verapamil with simvastatin (7.3% at 0.3 mg/kg, 9.3% at 1.0 mg/kg) were significantly higher than those in the control group (P < 0.05, 5.2%). The AUC and Cmax of norverapamil were not significantly increased in the rats coadministered with simvastatin compared with those in the control group. Moreover, the metabolite-parent ratio (M.R.) of norverapamil were significantly decreased in rats coadministered with simvastatin. These results implied that simvastatin significantly enhanced the oral bioavailability of verapamil by inhibiting the CYP3A-mediated metabolism in small intestine or in the liver and P-glycoprotein (P-gp) efflux pump in small intestine. Therefore, concurrent use of verapamil and simvastatin should be monitored closely to potential drug interactions for safe therapy of cardiovascular diseases.

Enhanced bioavailability of verapamil after oral administration with hesperidin in rats

The aim of this study was to investigate the effects of hesperidin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of hesperidin (3 or 10 mg/kg). Compared to the control group, the presence of hesperidin significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 71.1-96.8% and the peak concentration (C(max)) of verapamil by 98.3-105.2%. Hesperidin significantly (p<0.01) decreased the total plasma clearance (CL/F) of verapamil by 41.6-49.2% in rats. However there was no significant change in the time to reach the peak plasma concentration (T(max)), the elimination rate constant (K(el)) and the terminal half-life (T(1/2)) of verapamil in the presence of hesperidin. The AUC and C(max) of norverapamil were significantly (p<0.05) higher in rats co-administrated with hesperidin than those of the control. Consequently hesperidin significantly enhanced bioavailability of verapamil in rats. These results might be due to the decreased efflux and metabolism of verapamil in the intestine. Drug interactions should be concerned in the clinical setting when verapamil is used concomitantly with hesperidin or hesperidin-containing dietary.

Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

It has been reported that verapamil and atorvastatin are inhibitors of both P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A4, and verapamil is a substrate of both P-gp and CYP3A4. Thus, it could be expected that atorvastatin would alter the absorption and metabolism of verapamil. The pharmacokinetic parameters of verapamil and one of its metabolites, norverapamil, were compared after oral administration of verapamil (60 mg) in the presence or absence of oral atorvastatin (40 mg) in 12 healthy volunteers. Pharmacokinetics of verapamil were significantly altered by the coadministration of atorvastatin compared with those of without atorvastatin. For example, the total area under the plasma-concentration time curve to the last measured time, 24 h, in plasma (AUC(0-24) (h)) of verapamil increased significantly by 42.8%. Thus, the relative bioavailability increased by the same magnitude with atorvastatin. Although the AUC(0-24) (h) of norverapamil was not significantly different between two groups of humans, the AUC(0-24) (h, norverapamil)/ AUC(0-24) (h, verapamil) ratio was significantly reduced (27.5% decrease) with atorvastatin. The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.

Effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats

The present study aimed to investigate the effect of atorvastatin on the intravenous and oral pharmacokinetics of verapamil in rats. The pharmacokinetic parameters of verapamil were measured after an oral (9 mg/kg) or intravenous (3 mg/kg) administration of verapamil to rats in the presence and absence of atorvastatin. Compared with the control given verapamil alone, the concurrent use of 1.5 mg/kg of atorvastatin significantly increased the oral exposure of verapamil in rats. The AUC and C(max) of verapamil increased by 70% and 61%, respectively in the presence of atorvastatin (1.5 mg/kg), while there was no significant change in T(max) and the terminal plasma half-life (T(1/2)) of verapamil. Accordingly, the presence of atorvastatin significantly (p<0.05) increased the bioavailability of verapamil in rats. In contrast, atorvastatin had no effect on any pharmacokinetic parameters of verapamil given intravenously, implying that atorvastatin may improve the oral bioavailability of verapamil by reducing the prehepatic extraction of verapamil most likely mediated by P-gp and/or CYP3A4. In conclusion, coadministration of atorvastatin significantly enhanced the oral exposure of verapamil in rats without a change in the systemic clearance of intravenous verapamil, suggesting a potential drug interaction between verapamil and atorvastatin via the modulation of prehepatic extraction.

흰쥐에서 에피게로카테친의 장기투여가 베라파밀의 약물동태에 미치는 영향

Epigallocatechin gallate (EGCC), a flavonoid, is the main component of green tea extracts. EGCG has been reported to be an inhibitor of P-glycoprotein (P-gp) and cytochrom P450 3A(CYP3A4). This study investigated the effect of long-term administration of EGCG on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats pretreated with EGCG (7.5 mg/hg) for 3 and 9 days. Compared to oral control group, the presence of EGCG significantly (p by 134% (coad), 120% (3 days) and 66.1% (9 days). The absolute bioavailability (A.B.%) of verapamil was significantly (p and the time to reach the peak concentration of verapamil. Our results indicate that EGCG significantly enhanced oral bioavailability of verapamil in rats, implying that presence of EGCG could be effective to inhibit the CYP3A4-mediated metabolism and P-gp efflux of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with EGCG or EGCG-containing dietary.

The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80 mg, Isoptin) to 12 healthy male (mean age: 25.75+/-2.42 years, mean body weight: 70.59+/-9.94 kg) and 12 healthy female subjects (mean age: 24.08+/-2.84 years, mean body weight: 56.67+/-5.23 kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC(0-24) and AUC(0-infinity) ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible.