Plasma Concentrations Of Verapamil Research Articles

Pharmacokinetics of Verapamil and Hemodynamic Indices during Head-down Bed Rest

The purpose of this work was to study the pharmacokinetics of the Ca ion antagonist verapamil (a single dose of 80 mg) and hemodynamics in nine volunteers with normal life activities (experiment 1) and on the second day of head-down (–8°) bed rest (experiment 2). The plasma concentration of verapamil was measured using high-performance liquid chromatography with fluorometric detection. Heart rate (HR), cardiac output (CO), stroke volume (SV) and general peripheral vascular resistance (GPVR) were measured using integral rheography according to Tishchenko (Mingograf-410, Russia); blood pressure (BP) was measured by Korotkoff sounds. Analysis of verapamil pharmacokinetics in both experiments showed identity of the averaged curve profiles that did not differ significantly. The pharmacokinetic parameters were comparable. Based on hemodynamics analysis, HR elevation 1 h after verapamil administration was the most common reaction in both experiments; a short CO rise and GPVR decrease were observed in experiment 2 1 h after administration. These hemodynamic shifts were not pathologic and did not deviate from the physiological range in healthy people; changes in verapamil pharmacokinetics were also not detected. These findings provide the grounds to recommend verapamil for rational pharmacotherapy of cardiovascular diseases that may develop in piloted space missions.

Characterization of microminipigs as an in vivo experimental model for cardiac safety pharmacology

We pharmacologically characterized microminipigs as an in vivo experimental model by assessing cardiovascular effects of pilsicainide, verapamil and E-4031, which can preferentially inhibit cardiac Na+, Ca2+ and K+ channels, respectively. Intravenous infusion of 1 mg/kg of pilsicainide (n = 4), 0.1 mg/kg of verapamil (n = 4) and 0.01 followed by 0.1 mg/kg of E-4031 (n = 5) over 10 min decreased the heart rate, mean blood pressure and ventricular contractility. Moreover, pilsicainide prolonged the PR interval, QRS width and QTc; verapamil prolonged the PR interval, but shortened the QRS width and QTc; and E-4031 prolonged the QTc, whereas no substantial change was detected in the PR interval or QRS width. Peak plasma concentrations of pilsicainide, verapamil and E-4031 in microminipigs were 1.7–4.8 times higher than those expected in humans and dogs, possibly due to smaller effective volume of drug distribution. The extent of the drug-induced cardiovascular responses was generally greater in microminipigs than in humans and dogs, which could be explained by the following possibilities; namely unique pharmacokinetic profile, less great reflex-mediated increase of sympathetic tone and/or smaller repolarization reserve in microminipigs. These information may make it feasible to apply this new-type animal to a tool for assessing cardiac safety profiles of new chemical entities.

SP27-1 Risk pathogens and PK/PD of antibiotics

The aim of this work was to compare the suitability of different pharmacodynamic models for PK–PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension.A “shunt” microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg− 1). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified Emax model.No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK–PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK–PD parameters, linear and Emax model did not permit an accurate PK–PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified Emax model allows both a precise and accurate estimation of PK–PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK–PD parameters estimated for the hypotensive response.Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK–PD parameters estimation by using the linear and classical Emax model depends on the magnitude of concentration–effect curve covered in the study. Conversely, the modified Emax model allowed both a precise and accurate estimation of PK–PD parameters, suggesting that the modified Emax pharmacodynamic model is the most suitable for verapamil PK–PD modeling.

Drug−disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity

Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn's disease (CD), a disease for which the disease severity can be readily ranked. We administered 80 mg verapamil orally to (i) healthy control subjects (n= 9), (ii) patients with clinically quiescent CD (n= 22) and (iii) patients with clinically active CD (n= 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index. CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r= 0.86, P < 0.0006), CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein.

Pharmacokinetics of verapamil in diabetic rats induced by combination of high-fat diet and streptozotocin injection

The aim of this study was to investigate effects of type 2 diabetes on the pharmacokinetics of verapamil after intravenous administration.Diabetes mellitus (DM) rats were induced by combination of high-fat diet (HFD) and streptozotocin. Plasma concentrations of verapamil in DM rats, rats fed with HFD, and control (CON) rats were measured after intravenous administration of 1 mg/kg verapamil and corresponding pharmacokinetic parameters were estimated. Area under the plasma concentration in DM rats was significantly smaller than that in CON rats.In vitro microsomal study showed that intrinsic clearance of verapamil in DM rats was significantly higher than those in CON rats. Compared to CON rats, higher intrinsic clearance was also observed in HFD rats. Western blot results demonstrated higher levels of CYP3A2 in DM and HFD rats, which was in line to activity of CYP3A.All the results gave a conclusion that diabetes may enhance metabolism of verapamil in rat, and the enhancement may partly result from induction of CYP3A.

Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

The aim of this study was to report the effect of diabetes mellitus on the pharmacokinetics of verapamil in a route-dependent manner. Diabetes in rats was induced by streptozotocin. Plasma concentrations of verapamil and its metabolite, norverapamil, were measured after oral (10 mg/kg) or intravenous (1 mg/kg) administration. The concentrations of verapamil in portal plasma after oral administration were also determined. Norverapamil formation was used for assessing CYP3A activity in hepatic and intestinal microsomes of diabetic rats. The protein levels of CYP3A1 and CYP3A2 in liver and intestine were measured by Western blot. It was found that diabetes significantly increased the plasma concentration of verapamil and norverapamil after oral administration, which resulted in a 74% increase in the area under the concentration-time curve (AUC) of verapamil, but the ratio of AUC((norverapamil))/AUC((verapamil)) was significantly decreased by 38%. In contrast, diabetes significantly decreased the AUC of verapamil by 22% after intravenous administration. Diabetes also resulted in increased AUC of verapamil in portal vein by 3.8-fold compared with that in control rats. The absolute bioavailability of verapamil was higher than that of control rats. An in vitro study showed that increased CYP3A activity in the hepatic microsome and decreased CYP3A activity in the intestinal microsome were accompanied by an increase and decrease in the protein expression of CYP3A1/2 in liver and intestine of diabetic rats, respectively. In conclusion, diabetes mellitus revealed a tissue-specific effect on CYP3A activity and expression (induced in liver and inhibited in intestine), resulting in opposite pharmacokinetic behaviors of verapamil after oral and intravenous administration to diabetic rats.

The Effect of Licorice Drink on the Systemic Exposure of Verapamil in Rabbits

The effect of licorice root drink (aqueous extract of Glycyrrhiza glabra Fabaceae) on plasma concentration of verapamil, using rabbits as animal model, was investigated. Two groups of locally inbred New Zealand male rabbits were used. The first group was given a single dose of licorice drink (4 ml/kg body weight) concomitantly with 30 mg/kg verapamil, and the second group was given a daily dose of licorice drink (4 ml/kg body weight) for two weeks, with single doses of verapamil on days, 7 and 14. Single dose treatment resulted in a nonsignificant decrease in mean C(max) by 33.2% (P = 0.41), but in a significant decrease of AUC(0-24) and AUC(0-infinity) by 60.5% and 63.6%, respectively (P = 0.01). First period of multiple dose treatment study (7 days), resulted in a significant reduction in mean C(max), AUC(0-24) and AUC(0-infinity) by 55.0%, 47.0% and 45.7%, respectively (P = 0.02, 0.03 and 0.03, respectively). A more pronounced effect was seen at second period of multiple dose treatment study (14 days), where the corresponding decrease was, 85.4%, 76.8% and 73.3%, respectively (P < 0.01). Mean T(max) was significantly increased 4.2-fold over control period at day 14 of multiple dose study (P = 0.02). In conclusion, licorice root drink decreased verapamil systemic exposure both after single dose and after daily doses for 14 days.

CHRONOPHARMACOLOGY OF VERAPAMIL IN HYPERTENSION: PP.25.02

Objective: The aim of the trial was to study the pharmacokinetics of morning and evening intake of verapamil retard and to compare these data with 24-hour antihypertensive effect of the drug. Design and Method: 14 volunteers (5 males, mean age 62 ± 2 years) with stable hypertension (mean day-time blood pressure (BP) >135/85 mm Hg) were enrolled into the open, randomized, cross-over trial. Before the trial started, all antihypertensive medications were withdrawn, with an exception of short-acting agents. The duration of the initial wash-out period was 2 weeks; the duration of both “morning” and “evening” treatment courses – 3 weeks; the interval between courses - 1 week. The dose of verapamil (isoptin-SR) was 240 mg o.d. The plasma concentration of non-modified verapamil was measured by high-performance liquid chromatography with fluorescent detection. BP monitoring (Spacelabs 90207) was performed prior to treatment and at the end of each course of treatment, simultaneously with the verapamil concentration measurement. The Spearman partial coefficient with z-transformation was used in correlation analysis. Results: The maximal plasma concentration of verapamil after its morning intake was 239.7 ± 152.3 ng/ml (M ± SD), after the evening intake – 148.6 ± 107.4 ng/ml (p < 0,01). The half-elimination time was 12.5 ± 3.5 h and 22.6 ± 15.2 h (p < .05), respectively. We found no significant differences in other pharmacokinetic parameters. The correlation coefficients between 24 hour systolic BP changes and drug concentrations were -0.134 ± 0.050 for morning intake and -0.242 ± 0.081 for evening intake (p < 0,05). Conclusions: Morning intake of verapamil in hypertensive patients resulted in rapid increase of drug plasma concentration. At the same time, evening administration of verapamil was associated with higher half-elimination time and “concentration-effect” correlation. According to our data, the evening verapamil intake should be more effective and cause less adverse events. We propose that our analytical model may be used for the identification of the most rational time regimen of different antihypertensive drugs administration.

Effect of Huang-Lian-Jie-Du-Decoction on pharmacokinetics of verapamil in rats

The aim was to investigate the effect of Huang-Lian-Jie-Du-Decoction (HLJDD) on the pharmacokinetic behaviour of verapamil in rats. Rats orally received 3.33 g/kg of HLJDD extract for 14 days, and pharmacokinetics of verapamil was investigated after oral and intravenous verapamil. Norverapamil formation for assessing cytochrome P450 3A activity in hepatic and intestinal microsomes of the HLJDD-treated rats was investigated. The inhibitory effect of berberine on the formation of norverapamil in intestinal and hepatic microsomes was also evaluated. HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC(0-480) of verapamil and a 25% reduction in the AUC(0-480) of norverapamil after oral administration. However, HLJDD did not alter the pharmacokinetic behaviour of verapamil after intravenous administration. Norverapamil formation showed biphasic kinetics in both intestinal and hepatic microsomes. HLJDD treatment significantly decreased the intrinsic clearance of verapamil in intestinal microsomes, but had no effect on the hepatic metabolism of verapamil. Berberine also inhibited norverapamil formation in both intestinal and hepatic microsomes; the extent of inhibition was larger in intestinal microsomes. HLJDD displayed a route-dependent effect on the pharmacokinetics of verapamil in rats. HLJDD treatment increased the bioavailability of verapamil partly via inhibiting first-pass verapamil metabolism in the intestine.

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.

Influence of ABCB1 gene polymorphisms on the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects

To assess the association between polymorphisms of the ABCB1 gene and the pharmacokinetics of verapamil among healthy Chinese Han ethnic subjects. Based on polymorphisms of the ABCB1 gene at positions 2677 and 3435, 24 healthy male participants were divided into three groups: 2677GG/3435CC (n = 6), 2677GT/3435CT (n = 12) and 2677TT/3435TT (n = 6). Each subject had received a single oral dose of verapamil (80 mg) under fasting conditions. Multiple blood samples were collected over 24 h, and plasma concentrations of verapamil were determined by HPLC. Pharmacokinetic characteristics were compared between the different genotypic groups. The pharmacokinetics parameters of verapamil differed significantly among the three genotypic groups. AUC(last) was significantly lower among individuals with the 2677TT/3435TT (159.5 +/- 79.0 ng ml(-1) h) and 2677GT/3435CT (189.3 +/- 73.1 ng ml(-1) h) genotypes than those with the 2677GG/3435CC genotype (303.1 +/- 83.7 ng ml(-1) h) (P= 0.004 and P= 0.008, respectively). However, the CL/F value was higher among subjects with the 2677TT/3435TT (523.0 +/- 173.7 l h(-1)) genotype than those with the 2677GT/3435CT (452.2 +/- 188.6 l h(-1)) or 2677GG/3435CC (265.4 +/- 72.8 l h(-1)) genotypes. A significant difference was also found between the latter two groups (P= 0.034). In addition, the C(max) tended to be higher among subjects with the 2677GG/3435CC genotype than those with the 2677GT/3435CT or 2677TT/3435TT genotypes (42.2 +/- 3.9 vs 32.2 +/- 16.2 vs 38.1 +/- 13.7 ng ml(-1)). Our study showed for the first time that verapamil pharmacokinetics may be influenced by particular genetic polymorphisms of the ABCB1 gene among healthy Chinese Han ethnic subjects. An individualized dosage regimen design incorporating such information may improve the efficacy of the drug whilst reducing adverse reactions.

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.

Interactions Between Herbal Medicines and Prescribed Drugs

The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John's wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John's wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with antiepileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional drugs have been documented. While the significance of many interactions is uncertain, several interactions, particularly those with St John's wort, may have serious clinical consequences.

Influence of Controlled Rheumatoid Arthritis on the Action and Disposition of Verapamil: Focus on Infliximab

Active rheumatoid arthritis (RA), obesity, and old age are associated with reduced responsiveness to the calcium channel antagonist verapamil despite increased drug concentrations. The diminishing effect appears to be associated with the severity of inflammation. We examined pharmacodynamics and pharmacokinetics of verapamil in patients with controlled RA. Volunteers included RA patients in remission: 12 on infliximab, 8 on other antirheumatic therapy, and 12 healthy subjects. Verapamil plasma concentrations and selected inflammatory mediators as well as blood pressure and electrocardiographic parameters were recorded after a single 80-mg dose of verapamil. Inflammatory mediators were all below what is reported for active RA, confirming that RA was controlled. The tumor necrosis factor-alpha concentration, however, was significantly higher in the infliximab group compared with other groups and the literature value for active RA. No significant difference was observed between groups in terms of percentage prolongation of PR interval despite a trend toward a lower response in the RA groups, the mean plasma concentrations, and the total and unbound area under the curve of verapamil. However, the slope of the S-verapamil concentration-effect curve was steeper for controls compared with the RA patients. Remission from active disease appears to restore plasma protein levels and hepatic drug metabolism activity in patients with RA, resulting in relatively normal verapamil pharmacokinetics.

Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene

Toluene and verapamil are subject to extensive oxidative metabolism mediated by CYP enzymes, and their interaction can be stereoselective. In the present study we investigated the influence of toluene inhalation on the enantioselective kinetic disposition of verapamil and its metabolite, norverapamil, in rats. Male Wistar rats (n = 6 per group) received a single dose of racemic verapamil (10 mg/kg) orally at the fifth day of nose-only toluene or air (control group) inhalation for 6 h/day (25, 50, and 100 ppm). Serial blood samples were collected from the tail up to 6 h after verapamil administration. The plasma concentrations of verapamil and norverapamil enantiomers were analyzed by LC-MS/MS by using a Chiralpak AD column. Toluene inhalation did not influence the kinetic disposition of verapamil or norverapamil enantiomers (p > 0.05, Kruskal-Wallis test) in rats. The pharmacokinetics of verapamil was enantioselective in the control group, with a higher plasma proportion of the S-verapamil (AUC 250.8 versus 120.4 ng x h x mL(-1); p < or = 0.05, Wilcoxon test) and S-norverapamil (AUC 72.3 versus 52.3 ng x h x mL(-1); p < or = 0.05, Wilcoxon test). Nose-only exposure to toluene at 25, 50, or 100 ppm resulted in a lack of enantioselectivity for both verapamil and norverapamil. The study demonstrates the importance of the application of enantioselective methods in studies on the interaction between solvents and chiral drugs.

Dietary salt does not influence the disposition of verapamil enantiomers in relation to efflux transporter ABCB1 genetic polymorphism in healthy Korean subjects

To evaluate the effects of dietary salt on the stereoselective disposition of verapamil enantiomers in relation to the transporter ABCB1 2677GG/3435CC and 2677TT/3435TT haplotypes, ten healthy subjects were asked to take diets of three different salt levels for 7 days in a randomized, three-way crossover manner.The plasma concentrations of verapamil and norverapamil enantiomers were determined after a single oral dose of 240 mg verapamil on the last day of each phase. Pharmacokinetic parameters were calculated by non-compartmental analysis techniques and compared among the three different dietary salt phases.Compared with the medium salt diet, the high and low salt diets had no significant effect on the disposition of verapamil enantiomers. Moreover, the ABCB1 haplotypes did not alter the impact of dietary salt, although ABCB1 2677TT/3435TT subjects had slightly, but not significantly, higher Cmax and area under the curve (AUC) and lower Tmax for the verapamil enantiomers than did 2677GG/3435CC subjects in each salt phase.

Comparison of different pharmacodynamic models for PK–PD modeling of verapamil in renovascular hypertension

Introduction The aim of this work was to compare the suitability of different pharmacodynamic models for PK–PD modeling of verapamil cardiovascular effects in aortic coarctated rats (ACo), a model of renovascular hypertension. Methods A “shunt” microdialysis probe was inserted in a carotid artery of anaesthetized sham-operated (SO) and ACo rats for determination of verapamil plasma concentrations and their effects on blood pressure and heart rate after intravenous application (1 and 3 mg kg − 1 ). Correlation between verapamil plasma levels and their cardiovascular effects was established by fitting data to a linear, and a conventional and modified E max model. Results No differences in verapamil volume of distribution were observed between experimental groups. Whilst clearance increased with dose in SO rats, no differences were found in verapamil clearance in ACo comparing both dose levels. A good correlation between verapamil plasma unbound concentrations and their hypotensive and chronotropic effects was found in both experimental groups using the tested PK–PD models. Although all pharmacodynamic models allowed a precise estimation of verapamil PK–PD parameters, linear and E max model did not permit an accurate PK–PD parameter estimation for the hypotensive and chronotropic effect, respectively. Conversely, the modified E max model allows both a precise and accurate estimation of PK–PD parameters for verapamil effects. Although, absolute verapamil blood pressure lowering effect was greater in ACo rats compared with SO rats, no differences were found in verapamil PK–PD parameters estimated for the hypotensive response. Discussion Side-by-side comparison of the tested pharmacodynamic models showed that accuracy of PK–PD parameters estimation by using the linear and classical E max model depends on the magnitude of concentration–effect curve covered in the study. Conversely, the modified E max model allowed both a precise and accurate estimation of PK–PD parameters, suggesting that the modified E max pharmacodynamic model is the most suitable for verapamil PK–PD modeling.

Effects of angiotensin II blockade on inflammation‐induced alterations of pharmacokinetics and pharmacodynamics of calcium channel blockers

Inflammation elevates plasma verapamil concentrations but diminishes pharmacological response. Angiotensin II is a pro-inflammatory mediator. We examined the effect of angiotensin II receptor blockade on the pharmacokinetics and pharmacodynamics of verapamil, as well as the binding properties and amounts of its target protein in calcium channels, in a rat model of inflammation. We used 4 groups of male Sprague-Dawley rats (220-280 g): inflamed-placebo, inflamed-treated, control-placebo and control-treated. Inflammation as pre-adjuvant arthritis was induced by injecting Mycobacterium butyricum on day 0. From day 6 to 12, 30 mg kg(-1) oral valsartan or placebo was administered twice daily. On day 12, a single oral dose of 25 mg kg(-1) verapamil was administered and prolongation of the PR interval measured and plasma samples collected for verapamil and nor-verapamil analysis. The amounts of the target protein Ca(v)1.2 subunit of L-type calcium channels in heart was measured by Western blotting and ligand binding with (3)H-nitrendipine. Inflammation reduced effects of verapamil, although plasma drug concentrations were increased. This was associated with a reduction in ligand binding capacity and amount of the calcium channel target protein in heart extracts. Valsartan significantly reversed the down-regulating effect of inflammation on verapamil's effects on the PR interval, and the lower level of protein binding and the decreased target protein. Reduced responses to calcium channel blockers in inflammatory conditions appeared to be due to a reduced amount of target protein that was reversed by the angiotensin II antagonist, valsartan.

EFFECTS OF LIVER FIBROSIS ON VERAPAMIL PHARMACOKINETICS IN RATS

1. Liver fibrosis is the compensatory state of cirrhosis. In the long asymptomatic period, it is imperative to select a proper dosing regimen for drugs that are applicable to hepatic fibrosis owing to altered pharmacokinetics and bioavailability. The present study was designed to observe the changes in verapamil pharmacokinetics in rats with early liver fibrosis with respect to alterations in cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). 2. A rat liver fibrosis model was successfully established using several inducers, including a high-fat diet, alcohol and carbon tetrachloride. After rats received a single intravenous or oral dose of verapamil (5 mg/kg), the plasma concentrations of verapamil were determined at scheduled time-points using HPLC. The activity of hepatic and small intestinal microsomal erythromycin N-demethylase (a marker for CYP3A) and the expression of small intestinal cyp3a and multidrug resistance (mdr) mRNA were compared between normal rats and rats with liver fibrosis. 3. The results showed that when verapamil was administered intravenously, the area under the curve (AUC), elimination half-life (T((1/2)(K10))) and mean residence time (MRT) increased significantly, whereas clearance (Cl) decreased, in rats with liver fibrosis compared with normal rats. After oral administration of verapamil, the AUC, (T((1/2)(K10))) and maximum concentration (C(max)) increased, Cl decreased and the absorption half-life (T((1/2)(K01))) and time to peak concentration (T(max)) were unchanged compared with normal rats. The oral bioavailability of verapamil was 32.9% in normal rats and 34.4% in rats with liver fibrosis. Furthermore, decreased CYP3A activity in the liver was accompanied by upregulated cyp3a9/18 and unchanged mdr mRNA in the small intestine compared with normal rats. Expression of cyp3a9/18 and mdr mRNA in the intestine was significantly inhibited by verapamil. 4. The results suggest that the lowered Cl and increased AUC of verapamil after intravenous and oral administration in rats with liver fibrosis were due to downregulation of CYP3A in the liver. The absorption rate of verapamil in rats with liver fibrosis was unchanged because mdr was unchanged and cyp3a was inhibited in the intestine by verapamil itself. There was no notable difference in oral bioavailability between normal rats and rats with liver fibrosis.

Effect of calcium-channel antagonist on repolarization heterogeneity of ventricular myocardium in an in vitro rabbit model of long QT syndrome

Intracellular Ca(2+) and Ca(2+)-dependent signaling molecule play an essential role in the genesis of long-QT (LQT) syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repolarization heterogeneity of ventricular myocardium was assessed in an in vitro rabbit model of LQT syndrome. By using the monophasic action potential (MAP) recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall in rabbit hearts perfused by Langendorff method with standard Tyrode's solution. Bradycardia was induced by complete ablation of atrioventricular node. A catheter was introduced into the right ventricle to pace at the cycle lengths (CLs) of 1500, 1000, and 500 ms, successively. Quinidine (2 micromol/L) prolonged QT interval and ventricular MAP duration (MAPD), and increased transmural dispersion of repolarization (TDR) in a reverse rate-dependent fashion in isolated rabbit heart. No polymorphic ventricular tachycardias were induced under this condition. The effective free therapeutic plasma concentrations of verapamil (0.01-0.05 micromol/L) used in this experiment had no effect on quinidine-induced changes of QT interval, MAPD and TDR. This study demonstrated that, in this model of LQT syndrome, blockade of calcium-channel with verapamil had no effect on quinidine-induced changes of repolatiation heterogeneity of ventricular myocardium.