The effect of verapamil on the pharmacokinetics of paclitaxel in rats.

The purpose of this study was to investigate the effect of verapamil on the pharmacokinetic parameters of paclitaxel (50 mg/kg) when paclitaxel is co-administered with verapamil (1, 5, and 15 mg/kg) or pretreated with verapamil (5 mg/kg) for 0.5 h, 3 days, and 6 days orally in rats. When paclitaxel was either co-administered or pretreated with verapamil, the peak plasma concentrations (C(max)) of paclitaxel with verapamil were significantly higher (p<0.05 at 5 mg/kg and 0.5 h; p<0.01 at 15 mg/kg, 3 days and 6 days) than that of the control. The areas under the plasma concentration-time curve (AUC) of paclitaxel with verapamil were significantly (p<0.05 at 5 mg/kg and 0.5 h; p<0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control. The AUCs of paclitaxel were increased with verapamil in the dose dependent manner. The half-life (t(1/2)) of paclitaxel with verapamil was significantly prolonged compared with that of the control, except for 1 mg/kg co-administration. The absolute bioavailability of paclitaxel with verapamil (3.9-5.4%) was significantly (p<0.05 at 5 mg/kg and 0.5 h; p<0.01 at 15 mg/kg, 3 days and 6 days) higher than that of the control (2.2%). The relative bioavailability of paclitaxel pretreated with verapamil was higher than that of co-administration in rats. Based on these results, it might be considered that the pharmacokinetic parameters of paclitaxel was significantly affected by verapamil which is an inhibitor of the metabolizing enzyme (CYP3A4) in the intestinal mucosa and liver, and the p-glycoprotein efflux pump in the intestinal mucosa. If these results are confirmed in humans in a clinical setting, the paclitaxel dose should be adjusted when it is given concomitantly with verapamil.     

Effects of nifedipine, verapamil, diltiazem and trifluoperazine on the antinociceptive activity of acetaminophen

The influence of the calcium channel blockers (CCBs) nifedipine, verapamil and diltiazem, and the calmodulin antagonist trifluoperazine on the antinociceptive activity of acetaminophen was studied in male albino mice. The nociceptive response was determined by the acetic acid writhing test. Nifedipine (50 or 20 mg/kg), verapamil (20 mg/kg), diltiazem (70 mg/kg) and trifluoperazine (3 mg/kg) were administered orally alone or 1 h before acetaminophen (100 mg/kg). Nifedipine (50 mg/kg), verapamil, diltiazem and trifluoperazine administered alone demonstrated significant antinociceptive effects compared to controls. Nifedipine, verapamil, diltiazem and trifluoperazine applied 1 h before acetaminophen potentiated its antinociceptive activity, which was strongest in mice injected with verapamil and nifedipine (20 mg/kg). It was established that 1 h after nifedipine (50 mg/kg) treatment, cytochrome P450 content, NADPH cytochrome c reductase and ethylmorphine-N-demethylase (EMND) activities were increased in the liver microsomes. Verapamil, diltiazem and trifluoperazine did not change the drug metabolizing enzymes studied. It is assumed that their effect on acetaminophen analgesia is not associated with the changes in acetaminophen oxidative metabolism in the liver.     

Antihypertensive properties of the novel calcium antagonist (1S,2S)-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino] ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride in rat models of hypertension. Comparison with verapamil

(1S,2S)-2-[2-[[3-(2-Benzimidazolyl)propyl]methylamino]ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride (Ro 40-5967) is a novel calcium antagonist. Its effect on systolic arterial blood pressure and heart rate was investigated in comparison with verapamil in conscious spontaneously hypertensive rats (SHR), renal hypertensive rats (2K1C), deoxycorticosterone acetate (DOCA)-NaCl hypertensive rats and normotensive Wistar rats. After single oral doses, Ro 40-5967 (3-30 mg/kg) and verapamil (10-100 mg/kg) produced a dose-related decrease in blood pressure in all three types of hypertensive rats. Ro 40-5967 was 3-5 times more potent than verapamil. DOCA-NaCl hypertensive rats were more sensitive to the antihypertensive action of Ro 40-5967 than renal hypertensive rats and SHR. Both compounds lowered blood pressure of normotensive rats to a lesser degree than that of hypertensive rats. The antihypertensive effects of Ro 40-5967 and verapamil occurred fast, with similar efficacies and reached maximal values 3 and 6 h postdrug (SHR). While the significant antihypertensive effect of Ro 40-5967 (30 mg/kg) persisted for 24 h, that of verapamil (100 mg/kg) recovered completely 16 h postdrug. The experimental data suggest that Ro 40-5967 might be suitable for clinical use as a once-a-day antihypertensive agent.     

The effects of verapamil on stress- and histamine-induced gastric lesions in rats

The influence of verapamil on stress-induced and histamine-induced gastric ulcers was investigated in rats. The influence of verapamil was also examined on various biochemical parameters that affect the development of these ulcer models. The animals were pretreated with intraperitoneal verapamil (1, 5, 25 mg/kg) by injection 1 h before the induction of experimental ulceration. The gastric lesions were induced by cold-restraint stress or intraperitoneal injection of histamine (300 mg/kg). The gastroprotective effects of verapamil were evaluated by determining the ulcer index, gastric mucus content, free and total acidity, lipid peroxidation and non-protein sulfhydryl content. Verapamil pretreatment at a dose of 25 mg/kg significantly reduced stress-induced ulcers. Verapamil enhanced mucus secretion, reduced total acidity and lipid peroxidation and decreased non-protein sulfhydryl content in a dose-dependent fashion. On the other hand, pretreatment with verapamil at any dose had no significant effect on histamine-induced ulcers. L-Arginine (L-A) (100 mg/kg) or L-nitroarginine (L-NNA) (100 mg/kg) were also injected i.p. to the animals 1 h before stress to test the role of nitric oxide (NO) in the mechanism of the gastroprotective activity of verapamil (25 mg/kg). The results suggested that verapamil stimulates gastric NO production, but the overproduction of NO worsens gastric ulcers. The effects of verapamil on experimentally induced ulcers may be related to its ability to induce biochemical alterations in the parameters measured in gastric tissue.     

Blocking naloxone-precipitated withdrawal in rats and hamsters.

Three experiments studied the effects of putative antagonists of opiate withdrawal in hamsters and rats. In Experiment 1, the calcium channel antagonists verapamil (20 mg/kg) and nifedipine (20 mg/kg) failed to antagonize naloxone (1 mg/kg)-precipitated withdrawal in hamsters implanted with two 75-mg morphine pellets, whereas clonidine (0.4 mg/kg), the alpha 2-adrenergic agonist, blocked most withdrawal signs. In Experiment 2, clonidine (0.4 mg/kg) and verapamil (20 mg/kg) were tested against naloxone-precipitated withdrawal in hamsters made acutely dependent by a single injection of morphine (15 mg/kg). As in Experiment 1, clonidine but not verapamil was effective. In Experiment 3, the effects of verapamil on naloxone-precipitated withdrawal were studied in morphine-pelleted rats and hamsters. In rats implanted with two morphine pellets, verapamil (20 mg/kg) reversed naloxone-precipitated withdrawal. By contrast, in hamsters implanted with either one or two morphine pellets neither of two doses of verapamil (20 and 30 mg/kg) was effective. These results are discussed in terms of species' differences in sensitivity to calcium channel blockers.     

Effects of naloxone and verapamil in experimental amitriptyline poisoning in rats

The effects of verapamil and naloxone as potential antidotes for amitriptyline-induced cardiotoxicity were investigated in an experimental rat model. Amitriptyline was infused continuously at a dose of 37.5 mg/kg/h. After 15 minutes, the animals were given either naloxone (2 mg/kg + 3 mg/kg/h), verapamil (0.08 mg/kg + 0.08 mg/kg/h), or physiological saline. In the group given naloxone, a significant decrease in heart rate was seen. Although MAP and max dP/dT increased, there was no significant difference from controls. Naloxone did not decrease mortality. When the bolus dose of verapamil was given, a significant decrease in MAP and max dP/dT was obtained. Although the mean blood pressure was significantly higher in those animals treated with verapamil who survived 60 minutes, verapamil did not change the course of the amitriptyline poisoning. In conclusion, our findings indicate that naloxone lacks significant positive effects and that verapamil has an additional negative inotropic effect. Neither drug can be recommended for the treatment of amitriptyline poisoning.     

New treatment methods in verapamil poisoning: experimental studies

The aim of this study was to evaluate the effectiveness of the treatment with 4-aminopyridine (4-AP, potassium channel inhibitor) and Bay K 8644 (calcium channel activator) in experimentally evoked verapamil poisoning in rats and to compare the results of this treatment with the effectiveness of widely accepted methods (adrenaline, calcium compounds). The experiment was carried out on male and female Wistar rats which were divided into 4 experimental (A, B, C, D) and a control (K) groups. Rats were anesthetized and the abdominal aorta was cannulated for mean arterial pressure and heart rate measurements while caudal vein was cannulated for drug administration. All animals were infused with verapamil (150 mg/kg/h) until 50% reduction of mean arterial pressure and/or heart rate was observed. After verapamil, control animals were given 0.9% NaCl solution and the other groups received 687.5 mg/kg/h of calcium glucolactobionicum (group A), 0.3 mg/kg/h of adrenaline (group B), 2 mg/kg/h of 4-AP (group C) or 2 mg/kg/h of Bay K 8644 (group D). The mean blood pressure and heart rate was checked and ECG was recorded every 10 min. A statistically significant decrease in mortality compared with the control group was observed in animals treated with adrenaline (p < or = 0.05), Bay K 8644 (p < or = 0.01) and 4-AP (p < or = 0.005). The treatment of experimentally evoked poisoning in rats using 4-AP or Bay K 8644 resulted in fast receding of poisoning symptoms: increase in blood pressure and heart rate, receding of bradyarrhythmia and return of sinus rhythm. The results of the study suggest the usefulness of 4-AP and Bay K 8644 in the treatment of verapamil poisoning.     

Verapamil worsens ethanol-induced gastric ulcers in rats

The effect of verapamil on ethanol-induced gastric ulceration was investigated in rats. Orally administered ethanol (0.5 ml), 10, 20 or 40% v/v, dose dependently produced glandular lesions, ranging from petechiae to haemorrhagic ulcers. These lesions were worsened by verapamil (2, 4 or 8 mg/kg given intraperitoneally (i.p.) 30 min beforehand) in the 30 min and 2 h ethanol-exposure experiments. However, ethanol ulceration or its aggravation by verapamil was antagonised by calcium gluconate (112 or 224 mg/kg given per os (p.o.) 30 min before ethanol administration) in a dose-related manner. These findings suggest that intracellular calcium depletion in the gastric glandular mucosa may account for ethanol ulceration and the ulcer-aggravating action of verapamil.     

The influence of verapamil on the clastogenic effect of cyclophosphane in somatic cells from BALB/c and C57Bl/6 mice]

The method of chromosome aberration count in the bone marrow cells of male BALB/c and C57Bl/6 mice was used to study the influence of intraperitoneal injection of verapamil in doses of 0.1-10 mg/kg and its administration into the stomach in doses of 2.5-10 mg/kg on the clastogenic effect of cyclophosphamide (10 mg/kg intraperitoneally) in a single and repeated (5 times at intervals of 24 h) administration. In repeated administration in all the doses used, verapamil significantly intensified the mutagenic activity of cyclophosphamide in C57Bl/6 mice and in doses 10 mg/kg in BALB/c mice. A single intraperitoneal verapamil injection (0.1-0.4 mg/kg) caused a statistically increase in the clastogenic effect of cyclophosphan in mice of both strains. The same effect was encountered in intraperitoneal injection (2.5 mg/kg) and administration into the stomach (5 mg/kg) of the calcium antagonist in BALB/c mice. Thus, the effect of verapamil on cyclophosphamide clastogenic activity depends on the dose, method, and schedule of administration of the calcium antagonist.     

Influence of famotidine on verapamil pharmacokinetics in rats.

The effect of famotidine (4 mg/kg, p.o.) on the kinetic profile of co-administered verapamil (20 mg/kg(-1), p.o.) was studied in the rat. Plasma verapamil levels were collected serially for 12 h and measured using sensitive HPLC method. The pharmacokinetic parameters (elimination half-life, area under the plasma concentration-time curve, peak plasma levels and the times to attain these plasma levels) of verapamil were evaluated in the rat. The results indicate that co-administered famotidine did not significantly alter the pharmacokinetic profile of verapamil in the rat. The present finding suggests that famotidine may safely be co-administered with verapamil but clearly further studies in human subjects are needed to reliably rule out the potential interaction of these two drugs.     

The influence of verapamil on the gastric effects of stress in rats

The influence of verapamil on stress- or bethanechol-induced gastric effects was investigated in rats. Intraperitoneally injected verapamil (1, 2 or 4 mg/kg), given 30 min beforehand, dose-dependently prevented gastric glandular ulceration, mast cell degranulation and the increased stomach wall contractions evoked by restraint at 4 degrees C for 1 h. Gastric acid secretion, as well as ulceration in both the forestomach and glandular segment, produced by subcutaneously-injected bethanechol (3.2 mg/kg) were also inhibited. It is concluded that decreased amine release from the mast cells, stomach wall relaxation and reduced gastric acid were responsible for the ulcer-antagonising effects of the calcium-entry blocker. The possible antiulcer actions of verapamil are discussed in the light of present knowledge regarding calcium involvement in the various mechanisms thought to contribute to the pathophysiology of stress ulceration in rat stomachs.     

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.     

Evidence for time-dependent interactions between ritonavir and lopinavir/ritonavir plasma levels following P-glycoprotein inhibition in Sprague-Dawley rats

The interaction between verapamil, a P-glycoprotein (P-gp) inhibitor, with ritonavir and lopinavir/ritonavir (LPV/r) after acute and chronic treatment was investigated in rats. Rats were divided into 4 groups, viz. Group 1: ritonavir, 20 mg/kg/d (n=18), group 2: ritonavir, 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18), group 3: LPV/r, 80 and 20 mg/kg/d (n=17) and group 4: LPV/r, 80 and 20 mg/kg/d plus verapamil 5 mg/kg/d (n=18). Blood samples were collected after decapitation on days 1, 7 and 21. Lopinavir and ritonavir plasma levels were simultaneous determined by a validated LC/MS/MS method. The lower limit of quantification for both ritonavir and lopinavir was 0.078 μg/ml. Verapamil significantly increased ritonavir plasma levels, administered as monotherapy, following acute (p<0.005) and chronic treatment (day 21) (p<0.005). During acute (but not chronic) LPV/r treatment, verapamil also increased the lopinavir levels (p<0.05). A time or exposure dependent pharmacokinetic interaction was thus observed between verapamil and ritonavir whether administered alone or after the lopinavir-ritonavir combination (LPV/r). This interaction occurred most prominently after acute treatment, and became less pronounced over time. This study indicates the importance of a longer time frame to investigate enzyme based drug interactions in rat models.     

Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats

The objective of present investigation was to study the effect of verapamil on the pharmacokinetics of irinotecan in order to evaluate the role of P-glycoprotein (P-gp) in irinotecan disposition. An in vitro study using Caco-2 intestinal cell monolayer was first carried out to determine the effect of verapamil on the function of intestinal P-gp. Verapamil (25 mg/kg) was administered orally 2 h before irinotecan oral (80 mg/kg) or intravenous (20 mg/kg) dosing in female Wistar rats. Plasma and biliary samples were collected at specified time points from control and treated animals to determine irinotecan and its metabolite, SN-38 concentrations. Bi-directional transport and inhibition studies in Caco-2 cells indicated irinotecan to be a P-gp substrate and the function of intestinal P-gp was significantly inhibited in presence of verapamil. After oral irinotecan dosing, the mean area under the plasma concentration–time curve (AUC) was found to be 14.03 ± 2.18 μg h/ml which was increased significantly, i.e. 61.71 ± 15.0 μg h/ml when verapamil was co-administered (P < 0.05). Similarly, the mean maximum plasma concentration of irinotecan increased from 2.93 ± 0.37 μg/ml (without verapamil) to 10.75 ± 1.0 μg/ml (with verapamil) (P < 0.05). There was approximately 4–5-folds increase in apparent bioavailability. On the other hand, the intravenous irinotecan administration with verapamil resulted in small but statistically significant effect on AUC (10.76 ± 2.0 to 23.3 ± 3.8 μg h/ml; P < 0.05) and systemic clearance (1206.4 ± 159.7 to 713.5 ± 78.2 ml/(h kg)). In addition, SN-38 showed significant change in oral pharmacokinetic parameters and minor changes in intravenous pharmacokinetic profile. Biliary excretion curves of both irinotecan and SN-38 were lowered by verapamil. The mean percent of irinotecan excreted into bile over 5 h following intravenous and oral administration was found to be 8% and 1%, respectively, which was further reduced to half when treated with verapamil. These results are quite stimulating for further development of a clinically useful oral formulation of irinotecan based on P-gp inhibition.     

Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo

Aim:

20(S)-Ginsenoside Rh2 (Rh2) has shown potent inhibition on P-glycoprotein (P-gp), while most HIV protease inhibitors are both substrates and inhibitors of P-gp and CYP3A4. The aim of this study was to investigate the potential pharmacokinetic interactions between Rh2 and the HIV protease inhibitor ritonavir.

Methods:

The effects of Rh2 on the cellular accumulation and transepithelial transport of ritonavir were studied in Caco-2 and MDCK-MDR1 cells. Male rats were administered Rh2 (25 or 60 mg/kg, po) or Rh2 (5 mg/kg, iv), followed by ritonavir (25 mg/kg, po). The P-gp inhibitors verapamil (20 mg/kg, po) or GF120918 (5 mg/kg, po) were used as positive controls. The concentrations of ritonavir in plasma, bile, urine, feces and tissue homogenates were analyzed using LC-MS.

Results:

Rh2 (10 μmol/L) significantly increased the accumulation and inhibited the efflux of ritonavir in Caco-2 and MDCK-MDR1 cells, as verapamil did. But Rh2 did not significantly alter ritonavir accumulation or transport in MDCK-WT cells. Intravenous Rh2 significantly increased the plasma exposure of ritonavir while reducing its excretion in the bile, and oral verapamil or GF120918 also increased plasma exposure of ritonavir but without changing its excretion in the bile. Interestingly, oral Rh2 at both doses did not significantly change the plasma profile of ritonavir. Moreover, oral Rh2 (25 mg/kg) significantly elevated the ritonavir concentration in the hepatic portal vein, and markedly increased its urinary excretion and tissue distribution, which might counteract the elevated absorption of ritonavir.

Conclusion:

Rh2 inhibits the efflux of ritonavir through P-gp in vitro. The effects of Rh2 on ritonavir exposure in vivo depend on the administration route of Rh2: intravenous, but not oral, administration of Rh2 significantly increased the plasma exposure of ritonavir.     

Effects of the Ca2(+)-antagonists nifedipine, verapamil, flunarizine and of the calmodulin antagonist trifluoperazine on muscarinic cholinergic receptors in rat cerebral cortex

1. Studies were made of [3H]QNB binding to muscarinic receptors in a membrane fraction from the cerebral cortex of rats treated orally for 13 days with the Ca2(+)-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg), flunarizine (10 mg/kg) and with the calmodulin antagonist trifluoperazine (3 mg/kg). 2. The [3H]QNB binding capacity (Bmax) was decreased by three Ca2(+)-antagonists: nifedipine, verapamil and flunarizine, the decrease was most pronounced with nifedipine. 3. The decrease in the number of muscarinic receptors after nifedipine and flunarizine was accompanied by an increase in their affinity; verapamil decreased both the number and the affinity of muscarinic receptors. 4. The calmodulin antagonist trifluoperazine changed neither the number nor the affinity of muscarinic receptors. 5. It is suggested that continuous treatment with different Ca2+ or calmodulin antagonists leads to difference in character and degree of alterations in the basic characteristics of muscarinic receptors in rat cerebral cortex.     

Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in diazepam-dependent rats

The effects of two calcium channel blockers (verapamil and cinnarizine) were evaluated on diazepam withdrawal symptoms. Rats were made diazepam dependent by chronic treatment with daily injections of the drug, 20 mg/kg IP for 3 weeks. On abrupt termination of the drug, animals showed withdrawal hyperactivity that was assessed by autonomic, behavioural and motor signs. The peak effect was seen 3 days after the withdrawal of diazepam. On IP administration, verapamil and cinnarizine (10, 20 and 40 mg/kg) given on eight occasions at an interval of 12 h reversed the withdrawal-induced increase in spontaneous motor activity. Cinnarizine in higher doses (20 and 40 mg/kg) was found to be effective in suppressing the behavioural signs but verapamil did not show any protective effect against startle response and irritability. These results suggest that modulation of the calcium influx in the CNS might influence withdrawal.This study was presented in XIth International Congress of Pharmacology (IUPHAR) at Amsterdam (July 1–6, 1990)     

CALCIUM ANTAGONISTS AND HYPERTENSION

1. Calcium antagonists, including verapamil, are now used widely in the management of patients with hypertension. 2. Six weeks of chronic therapy with verapamil (50 mg/kg per day, orally) to produce a plasma level of 80-100 ng/ml in Sprague-Dawley rats depletes cardiac noradrenaline (NA) without apparently causing beta 1 adrenoceptor 'up' regulation. 3. The effect of verapamil on cardiac NA is rapidly reversed upon verapamil withdrawal. 4. Chronic therapy with nisoldipine (100 mg/kg per day, orally) had no effect on cardiac NA. 5. Verapamil (50 mg/kg per day, orally) and nisoldipine (100 mg/kg per day, orally) therapy for 6 weeks prevented the time-dependent increase in systolic blood pressure in SHR rats. 6. Binding studies with (-)[3H]-D888 (desmethoxyverapamil) indicated that the affinity of the phenylalkylamine binding sites is higher in hearts of SHR relative to hearts from age-matched (25 weeks) WKY and SD, without any change in density.     

Clinical pharmacokinetics of verapamil in patients with atrial fibrillation

Summary The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin^® 2 ml), and oral verapamil 80 mg (Isoptin^® 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination phase (t_1/2=5.79 h), corresponding to a plasma clearance of 0.26 1/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t_1/2=5.53 h). The oral bioavailability was 10.5%±7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atrial fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration — effect data from all the patients were pooled (r=0.59,n=71;p<0.0005).     

Effects of KR-30035, a novel multidrug-resistance modulator, on the cardiovascular system of rats in vivo and on the cell cycle of human cancer cells in vitro

The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular system in vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20: 0.320+/-0.052 and 0.034+/-0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1 phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 microM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weaker in vivo effects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.