Administration Of Verapamil Research Articles

Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II.

Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for anti-cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti-cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo. Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIδ expression and CaMKII activity following drug treatments. Acute administration of sunitinib decreased left ventricular (LV) dP/dtmax. Acute administration of isoprenaline increased LVdP/dtmax dose-dependently, while LVdP/dtmax was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIδ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIδ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIδ expression and CaMKII activity. Chronic sunitinib and imatinib treatment increased CaMKIIδ expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction.

Hepatic, gastric and intestinal first-pass effects of vitexin-2''-O-rhamnoside in rats by ultra-high-performance liquid chromatography.

Previous research in our laboratory found that the absolute bioavailability of vitexin-2''-O-rhamnoside (VR) was quite low at 4.89%. A rapid and sensitive UHPLC method using hesperidin as an internal standard was therefore developed and validated to investigate the reasons for this by determining VR in rat plasma after administering intravenously, intraportally (5 mg/kg), intraduodenally and intragastrically (40 mg/kg) to the rat model of the hepatic, gastric and intestinal first-pass effects. As only a high intestinal first-pass effect of VR was found, that is, there existed a low bioavailability of VR (2.40%), inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A), including verapamil, cyclosporin A and midazolam, and absorption enhancers, including bile salts and borneol, combined with VR, were instilled into duodenum to evaluate the effects on bioavailability of VR. The results demonstrated that area under the concentration-time curve (AUC) values of VR slightly increased after administration of verapamil, cyclosporin A and midazolam, indicating that CYP3A and P-gp do not play an important role in the first-pass effect in the intestine. AUC values of VR significantly increased after administering bile salts or borneol, indicating that the low bioavailability of VR was mainly related to its poor absorption in the intestine.

Оценка принадлежности мексидола к субстратам, ингибиторам или индукторам гликопротеина-P

На 18 половозрелых кроликах-самцах породы шиншилла изучена принадлежность препарата мексидол к числу субстратов, ингибиторов или индукторов гликопротеина-P. Для оценки принадлежности мексидола к субстратам гликопротеина-P изучали его концентрацию в плазме крови животных методом ВЭЖХ с УФ-детектированием до и после курсового введения рифампицина и верапамила в качестве соответственно индуктора и ингибитора транспортера. Влияние мексидола на функциональную активность гликопротеина-P в плазме крови кроликов оценивали по фармакокинетике его маркерного субстрата — фексофенадина, концентрацию которого определяли методом ВЭЖХ с УФ-детектированием. Установлено, что мексидол не является субстратом гликопротеина-P, но оказывает ингибирующее влияние на его функциональную активность.

Abstract W P259: Selective Intra-arterial Administration of Verapamil is Neuroprotective in Acute Ischemic Stroke

Despite the urgent need for better stroke therapies, experimental stroke treatments have largely failed to translate to stroke patients. In an effort to bridge this translational gap, we have concentrated our efforts on drugs that are already FDA approved and associated with treating stroke-associated pathophysiology, such as cerebral artery vasospasm, with the goal of repurposing them to protect brain tissue from ischemic injury. Verapamil, a calcium channel blocker, is one such drug that is often infused intra-arterially by neurosurgeons treating vasospasm that results in ischemia. In demonstrating a reliable and reproducible stroke mouse model ( transient middle cerebral artery occlusion, MCAo) with the addition of a retro-engineered IA drug delivery model mimicking the human condition, we were able to optimize the injection volume and flow rate for pharmacotherapy administration of verapamil. Through this direct route of administration we have shown a significant decrease (P<0.001) in infarct volume and trending towards significance an increase in behavioral outcome when comparing treated animals versus control. Perfusion studies did not show significant differences in perfusion to account for vasomotor changes as the likely mechanism for ischemia reduction. To further explore this, after 1 hour MCAo in three month old C57/Bl6 mice, we examined the potential neuroprotective effects of verapamil on post stroke day 3. Whole brains were harvested and flash frozen for cryostat sectioning and cellular staining to compare apoptosis, appearance of mature neurons, astrocyte activation and synaptic stability. Results suggest that IA administration of verapamil, more specifically than reducing infarct volume, is directly neuroprotective on brain parenchymal tissue at risk.

Abstract W MP6: SAVER I: Superselective Administration of VErapamil during Recanalization in Acute Ischemic Stroke. A Phase I Feasibility Study

Large vessel occlusive ischemic stroke results in high rates of morbidity and mortality. While intravenous t-PA and intra-arterial (IA) thrombectomy are mainstays in acute stroke therapy, clinical outcomes lag significantly behind improving rates of acute revascularization. Thus, there is a critical need for a novel adjunctive therapy to reduce stroke burden and to improve outcome. Previous neuroprotective drug studies failed due to long intervals between symptom onset and drug administration, lack of concordant thrombolytic revascularization, and lack of targeted administration to the affected vessel. Through a retro-engineered mouse model of large vessel stroke allowing concomitant recanalization and selective intra-arterial (IA) administration we previously evaluated verapamil, a calcium channel blocker (CCB) that is already safely injected intra-arterially (IA) for vasospasm. In this clinically relevant model, verapamil was highly neuroprotective when combined with vessel recanalization. Based on this data, we conducted a single-institution Phase I study to evaluate the feasibility and safety of superselective IA verapamil (10mg) administration immediately following mechanical thrombectomy. We collected information about demographics, location of the occlusion, last known normal time, time to and recanalization. Evaluation of CTA collateralization was performed using a previously a published grading scale (Souza et al. AJNR. 2012). The primary endpoint was symptomatic intracranial hemorrhage (ICH) within 24 hours post-procedure as defined by the Interventional Management Stroke (IMS) III Trial (Broderick et al. NEJM. 2013). Patients were monitored and graded at 3 months with the modified Rankin Score (mRS). Of the enrolled patients, none had a significant ICH, and none died as a direct result of the procedure. Clinical outcome results for patients were encouraging, and warrant further study. These results will be used to support a Phase II dose selection study.

Concomitant protective and therapeutic role of verapamil in chronic mercury induced nephrotoxicity in the adult rat: histological, morphometric and ultrastructural study.

IntroductionMercury intoxication is a widespread problem as mercury is used in the manufacture of thermometers, batteries and electrical switches. It forms one of the most diffusible environmental pollutants. Mercury has a nephrotoxic effect which could occur at low exposure levels. Verapamil could help in the treatment of mercuric toxicity. The aim of the study was to examine the protective and therapeutic effect of concomitant verapamil on chronic mercuric chloride nephrotoxicity. This was done through histological, morphometric and transmission electron microscopic studies.Material and methodsSixty adult male albino rats were used. The rats were divided into a control group and 4 experimental groups: group I (HgCl2), group II (concomitant HgCl2 and verapamil), group III (HgCl2 withdrawal) and group IV (HgCl2 withdrawal then verapamil treatment).ResultsChronic administration of HgCl2 resulted in cortical nephrotoxic effects in the form of glomerular sclerosis, acute tubular necrosis and interstitial inflammatory cellular infiltration which eventually ended in interstitial fibrosis. Concomitant use of verapamil with HgCl2 improved the previous pathological changes partially. The findings in group III were less severe compared to group IV. The persistence of the pathological findings in these groups reflects the irreversible nephrotoxic changes caused by chronic HgCl2 exposure.ConclusionsWe concluded that the concomitant administration of verapamil has a much better effect in minimizing the nephrotoxic effect caused by chronic HgCl2 than its therapeutic administration. So, we recommended the prophylactic use of verapamil in suspected cases of chronic mercuric chloride nephrotoxicity to preserve renal function.

On a sugary-relationship between caspases and lamins

On a sugary-relationship between caspases and lamins

Oral verapamil in paroxysmal supraventricular tachycardia recurrence control: a randomized clinical trial.

Adenosine is the first-line medication in patients with paroxysmal supraventricular tachycardia. Because it is cleared so rapidly from the circulation, recurrence of paroxysmal supraventricular tachycardia after initial successful conversion may occur. This study was conducted to evaluate the role of oral verapamil administration to control early recurrences of paroxysmal supraventricular tachycardia after adenosine infusion. Patients with acute paroxysmal supraventricular tachycardia and no contraindications for adenosine or verapamil treatment were included in study. All patients received an adenosine protocol (6 mg rapid bolus intravenous injection followed by two repeated doses of 12 mg if necessary). Patients in the adenosine-only group did not received any other medications but patients in the adenosine/verapamil group received 40 mg verapamil orally immediately after converting the rhythm to sinus rhythm. All patients were followed up for 6 h in the acute care area of the emergency department under continuous cardiac monitoring. A total of 113 patients were assessed for eligibility and 92 patients were randomized into two groups (adenosine only versus adenosine/verapamil). There was no statistically significant difference in paroxysmal supraventricular tachycardia recurrence rate between the two groups in the first 30 min after treatment. Recurrence rate was statistically significantly lower in the adenosine/verapamil group than in the adenosine-only group between 30 and 120 min after treatment and thereafter. Two patients in the adenosine-only group experienced flushing and one patient in the adenosine/verapamil group experienced decreased systolic blood pressure. Oral verapamil can decrease paroxysmal supraventricular tachycardia recurrence after successful control with intravenous adenosine.

P2Y13 receptor-mediated rapid increase in intracellular calcium induced by ADP in cultured dorsal spinal cord microglia.

P2Y receptors have been implicated in the calcium mobilization by the response to neuroexcitatory substances in neurons and astrocytes, but little is known about P2Y receptors in microglia cells. In the present study, the effects of ADP on the intracellular calcium concentration ([Ca(2+)]i) in cultured dorsal spinal cord microglia were detected with confocal laser scanning microscopy using fluo-4/AM as a calcium fluorescence indicator that could monitor real-time alterations of [Ca(2+)]i. Here we show that ADP (0.01-100 μM) causes a rapid increase in [Ca(2+)]i with a dose-dependent manner in cultured microglia. The action of ADP on [Ca(2+)]i was significantly blocked by MRS2211 (a selective P2Y13 receptor antagonist), but was unaffected by MRS2179 (a selective P2Y1 receptor antagonist) or MRS2395 (a selective P2Y12 receptor antagonist), which suggest that P2Y13 receptor may be responsible for ADP-evoked Ca(2+) mobilization in cultured microglia. P2Y13-evoked Ca(2+) response can be obviously inhibited by BAPTA-AM and U-73122, respectively. Moreover, removal of extracellular Ca(2+) (by EGTA) also can obvious suppress the Ca(2+) mobilization. These results means both intracellular calcium and extracellular calcium are potentially important mechanisms in P2Y13 receptor-evoked Ca(2+) mobilization. However, P2Y13 receptor-evoked Ca(2+) response was not impaired after CdCl2 and verapamil administration, which suggest that voltage-operated Ca(2+) channels may be not related with P2Y13-evoked Ca(2+) response. In addition, Ca(2+) mobilization induced by ADP was abolished by different store-operated Ca(2+) channels (SOCs) blocker, 2-APB (50 μM) and SKF-96365 (1 mM), respectively. These observations suggest that the activation of P2Y13 receptor might be involved in the effect of ADP on [Ca(2+)]i in cultured dorsal spinal cord microglia. Furthermore, our results raise a possibility that P2Y13 receptor activation causes Ca(2+) release from Ca(2+) store, which leads to the opening of SOCs.

Effect of verapamil and nitroglycerin on transplanted lung function in canines

To investigate the protective effect of combined administration of verapamil and nitroglycerin on the function of canine transplanted lungs. Twenty orthotopic left lung transplantations were performed in 40 canines, which were randomly divided into 4 groups. In group I (control), the donor lungs were perfused and preserved with LPD solution, while group II with LPD solution plus verapamil 0.1 g/L, group III with LPD solution plus nitroglycerin 0.1g/L, and group IV with LPD solution plus verapamil 0.1 g/L and nitroglycerin 0.1 g/L. Hemodynamics and graft gas exchange were assessed 0, 2 and 4 h after the operation. The lung grafts were harvested to measure the wet/dry weight ratio, malondialdehyde (MDA) contents and superoxide dismutase (SOD) activity. Compared with group I, II and III, the mean pulmonary artery pressure (MPAP), pulmonary vascular resistance index (PVRI), partial pressure of oxygen in arterial blood (PaO₂), dynamic compliance (Cdyn) and alveolar-arterial oxygen tension volume [P(A- a)O₂] in group IV were improved significantly (P<0.05). No significant difference in the partial pressure of carbondioxide (PaCO₂) and peak inspiratory pressure (PIP) was observed in the 4 groups (P>0.05). In group IV, the wet/dry weight ratio and MDA contents were lower than those in the other 3 groups, and the SOD activity was significantly higher than that of the other 3 groups (P<0.05). Verapamil and nitroglycerin in LPD solution can protect the respiratory function of canine lung grafts by attenuating pulmonary edema and oxidative stress.

Reversible tachycardia mediated cardiomyopathy after radiofrequency ablation of idiopathic left ventricular tachycardia

A 20-year-old girl was admitted to our hospital with a chief complain of 12-days of palpitation and progressive shortness of breath. The symptoms of heart failure were consistent with New York Heart Association (NYHA) grade III. She had fever and cold symptoms 2-days before the onset of palpitation and heart failure symptoms but recovered soon, without other significant medical history. Physical examination demonstrates a heart rate of 170 beats per minute (bpm), a blood pressure of 70/40 mm Hg and bibasilar rales. ECG revealed a relatively narrow QRS tachycardia of 170 bpm with right bundle branch block (RBBB) morphology and a superior left axis configuration (Fig. 1a ). At the emergency department, empirical administration of intravenous verapamil was implemented and sinus rhythm was restored within 3 min with inverted T wave in leads II, III, aVF and V3–6 (Fig. 1b). A chest X-ray revealed bilateral plural effusion and increased cardiothoracic ratio (Fig. 2a ). Transthoracic echocardiography performed demonstrated marginal left ventricular dysfunction (left ventricular ejection fraction [LVEF] of 50%), with a normal LV end-diastolic diameter (LVEDD) of 38 mm and cardiac effusion with a fluid sonolucent area of 6 mm. Electrophysiological study performed in the following day after administration induced narrow QRS tachycardia which did not replicate the clinical morphology and indicated atrio-ventricular tachycardia via left atrio-ventricular bypass (Fig. 3a ), while the tachycardia of clinical morphology was not induced. The atrio-ventricular bypass was successfully ablated and the pre-systolic Purkinje potentials (Fig. 3b) were targeted, resulting in a new Q wave in inferior leads of ECG which mimics left posterior fascicular block after ablation (Fig. 1c). Chest X-ray performed in the 2nd day (Fig. 2b), the 3rd day (Fig. 2c) and the 40th day (Fig. 2d) revealed decreased and demission of plural effusion and decrease cardiothoracic ratio. Transthoracic echocardiography performed in the 3rd day demonstrated normalization of left ventricular dysfunction (LVEF of 76.6%) and cardiac effusion with a fluid sonolucent area of 6 mm, while in the 40th day the cardiac effusion was diminished. ECG in the 40th day revealed T wave restored upright (Fig. 1d). The patient remained free from arrhythmia for 2 months, without anti-arrhythmic medication.

Innovative approach to preparing radial artery cocktails in response to manufacturer shortages of nitroglycerin and verapamil.

Transradial access has gained popularity over transfemoral access for cardiac catheterization, because of the decreased risk of bleeding, time to ambulation, and length of stay leading to improved patient satisfaction. One disadvantage of the radial artery approach is vasospasm, which can be prevented with the administration of verapamil and nitroglycerin in a pre- and postradial cocktail. Unfortunately, there have been manufacturer shortages for both of these medications. The utilization of radial artery cocktails and other nitroglycerin compounding practices were evaluated in response to cost containment and waste reduction initiatives and to medication shortages. A modified process for supplying verapamil and nitroglycerin for the transradial approach via separate syringes enabled physicians to have quick access to the medications and to customize the cocktail based on the patient's needs. This process also decreased costs and minimized wastage. The change in practice decreased waste from 44% for preradial cocktail syringes and 66% for postradial cocktail syringes to 8.7%. This process for supplying the medications necessary to perform a radial artery catheterization and intracoronary nitroglycerin has allowed for conservation of commercial product supply.

Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.

In vitro and in vivo evidence for amphotericin B as a P-glycoprotein substrate on the blood-brain barrier.

Amphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cells in vitro was significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected with Cryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0; P < 0.05) and 30 min (5.2 versus 2.8; P < 0.05) after administration of verapamil or 45 min (6.0 versus 3.9; P < 0.05) and 60 min (5.4 versus 3.8; P < 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P < 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.

Need for prophylactic application of verapamil in transradial coronary procedures: a randomized trial. The VITRIOL (is Verapamil In TransRadial Interventions OmittabLe?) trial.

BackgroundVerapamil is traditionally applied prophylactically in transradial procedures to prevent radial artery spasm. However, verapamil may have side effects and is contraindicated in some clinical settings.Methods and ResultsDuring an investigator‐initiated, randomized, double‐blind trial, we evaluated the need for preventive verapamil administration. After vascular access was established, patients received either 5 mg verapamil (n=297) or placebo (n=294). We compared the rate of access site conversions as primary end point using a superiority margin of 5%. Occurrence of code breaks (composite of conversions and unplanned use of verapamil), overall verapamil use, procedural and fluoroscopic times, contrast volume, and subjective pain were investigated as secondary end points. The rate of access site conversions was not different in the 2 arms (placebo 1.7% versus verapamil 0.7%, P=0.28, difference 1.0%, 95% CI for the difference −1.1% to 3.3%). Proportion of code breaks was similar in the 2 groups (3.4% versus 1.3%, P=0.11), whereas overall verapamil use was markedly lower in the placebo arm (2.0% versus 100%, P<0.0001). Procedural time (median [IQR] 16.0 minutes [9.0 to 30.0 minutes] versus 17.0 minutes [10.0 to 31.0 minutes], P=0.37), fluoroscopic time (4.4 minutes [2.1 to 9.6 minutes] versus 4.8 minutes [2.4 to 10.7 minutes], P=0.28), contrast volume (72.5 mL [48.0 to 146.0 mL] versus 75.5 mL [47.0 to 156.5 mL], P=0.74), and pain score (P for trend=0.12) were comparable in the 2 groups.ConclusionsThe preventive use of verapamil may be unnecessary for transradial procedures. The omission of prophylactic verapamil may not only reduce the rate of potential complications related to the drug but also allow the safe extension of the transradial method to those with contraindications to verapamil.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01402427.

Effectiveness and Safety of Paramedic Administration of Verapamil and Adenosine for the Treatment of Supraventricular Tachycardia: A Review of the Literature

Introduction Adenosine and verapamil are the most commonly used pharmacological agents to treat supraventricular tachycardia (SVT). This review aims to identify the effectiveness and safety of pre-hospital use of adenosine and verapamil by paramedics. Methods A comprehensive electronic literature search was conducted. Studies of pre-hospital comparative effectiveness of adenosine and verapamil were included for further analysis. Studies where individual effectiveness of either verapamil or adenosine was reported in either the medical or pre-hospital setting were excluded. Animal studies and those articles unavailable in English were also excluded. Results Two pre-hospital studies were identified. Verapamil demonstrated greater reversion effectiveness across both studies, with side effects more commonly reported in the adenosine arm of each. The duration and severity of side effects resulting from verapamil administration was greater than that of adenosine. Paramedic electrocardiogram (ECG) interpretation was questionable, resulting in a number of errors across both studies. Conclusion Available studies report that verapamil is more effective for pre-hospital SVT reversion. Effective pre-hospital drug therapy for SVT must incorporate a measure of patient impact with regard to severity, duration and interventions required to correcting adverse effects. A larger contemporary study is required to further evidence paramedic use of pharmacological agents to treat SVT. Paramedic ECG interpretation is a key factor influencing correct treatment, and adequate education must form the basis of pre-hospital guidelines for SVT management.

Investigation of the functional role of P-glycoprotein in limiting the oral bioavailability of lumefantrine.

In the quest to explore the reason for the low and variable bioavailability of lumefantrine, we investigated the possible role of P-glycoprotein (P-gp) in lumefantrine intestinal absorption. An in situ single-pass intestinal perfusion study in rats with the P-gp inhibitor verapamil or quinidine and an ATPase assay with human P-gp membranes indicated that lumefantrine is a substrate of P-gp which limits its intestinal absorption. To confirm these findings, an in vivo pharmacokinetic study was performed in rats. The oral administration of verapamil (10 mg/kg of body weight) along with lumefantrine caused a significant increase in its bioavailability with a concomitant decrease in clearance. The increase in bioavailability of lumefantrine could be due to inhibition of P-gp and/or cytochrome P450 3A in the intestine/liver by verapamil. However, in a rat intestinal microsomal stability study, lumefantrine was found to be resistant to oxidative metabolism. Further, an in situ permeation study clearly showed a significant role of P-gp in limiting the oral absorption of lumefantrine. Thus, the increase in lumefantrine bioavailability with verapamil is attributed in part to the P-gp-inhibitory ability of verapamil. In conclusion, lumefantrine is a substrate of P-gp, and active efflux by P-gp across the intestine partly contributed to the low/variable bioavailability of lumefantrine.

Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs

The pharmacokinetics (PK) of fexofenadine (FEX) in pigs were investigated with the focus on exploring the interplay between hepatic transport and metabolism when administered intravenously (iv) alone or with verapamil. The in vivo pig model enabled simultaneous sampling from plasma (pre-liver, post-liver and peripheral), bile and urine. Each animal was administered FEX 35mg iv alone or with verapamil 35mg. Plasma, bile and urine were analyzed with liquid chromatography–tandem mass spectrometry. Non-compartmental analysis (NCA) was used to estimate traditional PK parameters. In addition, a physiologically based pharmacokinetic (PBPK) model consisting of 11 compartments (6 tissues +5 sample sites) was applied for mechanistic elucidation and estimation of individual PK parameters. FEX had a terminal half-life of 1.7h and a liver extraction of 3%. The fraction of the administered dose of unchanged FEX excreted into the bile was 25% and the bile exposure was more than 100 times higher than the portal vein total plasma exposure, indicating carrier-mediated (CM) disposition processes in the liver. 23% of the administered dose of FEX was excreted unchanged in the urine. An increase in FEX plasma exposure (+50%) and a decrease in renal clearance (−61%) were detected by NCA as a direct effect of concomitant administration of verapamil. However, analysis of the PBPK model also revealed that biliary clearance was significantly inhibited (−53%) by verapamil. In addition, PBPK analysis established that metabolism and CM uptake were important factors in the disposition of FEX in the liver. In conclusion, this study demonstrated that CM transport of FEX in both liver and kidneys was inhibited by a single dose of verapamil.

Application of permeability‐limited physiologically-based pharmacokinetic models: Part II-prediction of p‐glycoprotein mediated drug–drug interactions with digoxin

Digoxin is the recommended substrate for assessment of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) in vivo. The overall aim of our study was to investigate the inhibitory potential of both verapamil and norverapamil on the P-gp-mediated efflux of digoxin in both gut and liver. Therefore, a physiologically-based pharmacokinetic (PBPK) model for verapamil and its primary metabolite was developed and validated through the recovery of observed clinical plasma concentration data for both moieties and the reported interaction with midazolam, albeit a cytochrome P450 3A4-mediated DDI. The validated inhibitor model was then used in conjunction with the model developed previously for digoxin. The range of values obtained for the 10 trials indicated that increases in area under the plasma concentration-time curve (AUC) profiles and maximum plasma concentration observed (Cmax ) values of digoxin following administration of verapamil were more comparable with in vivo observations, when P-gp inhibition by the metabolite, norverapamil, was considered as well. The predicted decrease in AUC and Cmax values of digoxin following administration of rifampicin because of P-gp induction was 1.57- (range: 1.42-1.77) and 1.62-fold (range: 1.53-1.70), which were reasonably consistent with observed values of 1.4- and 2.2-fold, respectively. This study demonstrates the application of permeability-limited models of absorption and distribution within a PBPK framework together with relevant in vitro data on transporters to assess the clinical impact of modulated P-gp-mediated efflux by drugs in development.

Anti-Arrhythmic Effect of Verapamil Is Accompanied by Preservation of Cx43 Protein in Rat Heart

The present study was to test the hypothesis that anti-arrhythmic properties of verapamil may be accompanied by preserving connexin43 (Cx43) protein via calcium influx inhibition. In an in vivo study, myocardial ischemic arrhythmia was induced by occlusion of the left anterior descending (LAD) coronary artery for 45 min in Sprague-Dawley rats. Verapamil, a calcium channel antagonist, was injected i.v. into a femoral vein prior to ischemia. Effects of verapamil on arrhythmias induced by Bay K8644 (a calcium channel agonist) were also determined. In an ex vivo study, the isolated heart underwent an initial 10 min of baseline normal perfusion and was subjected to high calcium perfusion in the absence or presence of verapamil. Cardiac arrhythmia was measured by electrocardiogram (ECG) and Cx43 protein was determined by immunohistochemistry and western blotting. Administration of verapamil prior to myocardial ischemia significantly reduced the incidence of ventricular arrhythmias and total arrhythmia scores, with the reductions in heat rate, mean arterial pressure and left ventricular systolic pressure. Verapamil also inhibited arrhythmias induced by Bay K8644 and high calcium perfusion. Effect of verapamil on ischemic arrhythmia scores was abolished by heptanol, a Cx43 protein uncoupler and Gap 26, a Cx43 channels inhibitor. Immunohistochemistry data showed that ischemia-induced redistribution and reduced immunostaining of Cx43 were prevented by verapamil. In addition, diminished expression of Cx43 protein determined by western blotting was observed following myocardial ischemia in vivo or following high calcium perfusion ex vivo and was preserved after verapamil administration. Our data suggest that verapamil may confer an anti-arrhythmic effect via calcium influx inhibition, inhibition of oxygen consumption and accompanied by preservation of Cx43 protein.