Oral Dose Of Verapamil Research Articles

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 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.

Toxicologic and pharmacokinetic study of low doses of verapamil combined with doxorubicin

The effect of a chronic treatment with low oral doses of verapamil, a calcium channel blocker commonly employed in cardiovascular therapy, on doxorubicin toxicity, was evaluated in CD1 mice. Verapamil, administered at a dosage corresponding to a typical cardiovascular posology in humans, significantly increased doxorubicin toxicity. In particular the mortality was significantly higher and earlier and histological analysis revealed an increase in the severity of lesions in the liver, kidney and small bowel of verapamil pretreated animals. The pharmacokinetic profiles revealed that verapamil treated group had higher doxorubicin peak plasma and tissue levels and AUCs. This study shows that verapamil, administered at low doses, dramatically increases doxorubicin toxicity, probably through an interaction between the two drugs, both P-glycoprotein substrates, on the protein expressed in normal tissues, and suggests caution in the use of the calcium channel blocker for cardiovascular pathologies in patients who have to be treated with antineoplastic agents, substrates of P-glycoprotein.

Verapamil-induced gingival hyperplasia in children

Gingival hyperplasia (GH) occurs in 20 % to 40 So of all patients receiving long-term oral phenytoin therapy and phenytoin is probably the most common cause of GH in children and young ado1escents.l Several other drugs including nifedipine, a calcium channel blocker, have been reported infrequently to cause GH.2-4 We report here a similar GH in two children following the long-term administration of a large dose of verapamil for the management of supraventricular tachycardia (SVT). Verapamil-associated GH has not been reported previously in the English literature. Case Ntj. 1. SL is a 12-year-old girl who was first noted to have tachycardia during the prenatal period. She had a trial of digoxin, quinidine, and propranolol in high doses in various combinations, with partial control of her SVT. At 3 years of age, a diagnosis of a permanent form of junctional reciprocating tachycardia (long R-P’ tachycardia) was made by electrophysiologic study, and an intravenous verapamil trial (0.2 mg/kg) was successful. She had no ventricular dysfunction by echocardiography. She was started on oral verapamil, 80 mg twice a day (9 mg/kg/day), with partial control, and was maintained on a similar dose with respect to body weight for the next 4 years. At 7 years of age, she was changed to sustained-release verapamil, 240 mg twice a day (15 mg/kg/day). Following 2 weeks of therapy on this dose, her verapamil level was 1030 Fg/L and 590 PglL at 6 hours and 12 hours, respectively, after the oral dose of verapamil (therapeutic trough level 100 to 600 pg/ L). Following 6 weeks of verapamil therapy, she developed marked GH. The labial gingivae of the anterior maxillary and mandibular teeth were firm, red, and nodular, with minimal bleeding. Despite good dental hygiene and frequent dental visits, she had persistent GH. There were no other adverse effects of verapamil. At 11 years of age verapamil was discontinued because of partial control of the tachycardia. Six weeks later her GH significantly improved. Subsequently she was started on a regimen of oral propafenone without success. At present she is maintained on a regimen of oral Aecainide with fairly good control of the tachycardia. Case No. 2. DM is a 16-year-old young woman patient who was noted to have a tachycardia during the prenatal

The effect of three different oral doses of verapamil on the disposition of theophylline

Results of previous studies suggest that the theophylline-verapamil drug interaction may be dependent on verapamil dose. Therefore, in a randomized four-way cross over study, 12 healthy males received theophylline, as a single intravenous dose of aminophylline, alone (phase I) and after a four day regimen of oral verapamil 40 mg (phase II), 80 mg (phase III), and 120 mg (phase IV) every 8 h. Serial blood samples were collected over a 24 hour period for determination of serum theophylline concentration and subsequent pharmacokinetic analysis. Mean theophylline AUC for phase I-IV was 93.6, 105.6, 110.8, 120.1 mg.h.l-1, respectively. Mean theophylline clearance for phase I-IV was 3.89, 3.59, 3.35, and 3.20 l.h-1, respectively. The changes in AUC, clearance, and lambda z were linearly correlated to verapamil dose. These results suggest that the inhibitory effect of verapamil on the pharmacokinetic disposition of theophylline is directly related to verapamil dose.

Verapamil in the prophylaxis of bronchial asthma

A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced broncho-constriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (delta PD20FEV1Hi greater than 100%) in the responders 5 h after the oral dose. The relationship of the bronchoprotective effect to the plasma level of verapamil was also examined. Responders and non-responders did not differ significantly in the peak plasma level or the time course of the plasma verapamil concentration. The protective effect was not correlated with the peak plasma level of verapamil or with the baseline bronchial hyperreactivity.

Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.

1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double-blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre-treatment with propranolol. When verapamil and propranolol were co-administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8-38%) but the measured increase after the combination was 40% (95% C.I. 26-54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was observed after repeated doses. 7. These findings provide little evidence of a pharmacodynamic or pharmacokinetic interaction between verapamil and propranolol in normal subjects. Most of the haemodynamic responses to these drugs in combination can be explained by additive drug effects but an interaction affecting AV conduction after repeated doses cannot be excluded. The minor pharmacokinetic interaction between the drugs is unlikely to be relevant to the pharmacodynamic changes.

Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

The effect of calcium channel blockers on the progression of renal failure is controversial. In contrast with earlier studies, we recently reported that moderately large doses of verapamil significantly accelerated chronic renal failure in the rat remnant kidney model. Studies reporting beneficial effects of verapamil were characterised by a much lower dose of verapamil and by the start of treatment immediately after renal ablation, which potentially interfered with the initial phase of remnant kidney hypertrophy. We therefore studied the effects of a high, fully antihypertensive oral dose of verapamil (100-150 mg/kg/per day; group Vera high) and a low, haemodynamically almost ineffective dose (10-15 mg/kg per day; group Vera low), on the progression of chronic renal failure in female Wistar rats with 5/6 nephrectomy. The treatment was started no earlier than 5 weeks after renal ablation, and matched groups of 20 animals were followed for 16 weeks thereafter. High-dose verapamil reduced systolic blood pressure to median values of 130-140 mmHg throughout the experimental period, whereas blood pressure in Vera low animals remained elevated at median values of 165-172 mmHg similar to non-treated rats with 172-185 mmHg median systolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

A Double-Blind, Randomized, Crossover Comparison of Equivalent (by Weight) Oral Doses of Verapamil and Diltiazem in Patients with Mild to Moderate Hypertension

Hollifield, John W.; Heusner, James J.*; DesChamps, Mary K.; Gray, James† Author Information

Near-total Reduction in Verapamil Bioavailability by Rifampin: Electrocardiographic Correlates

We evaluated the significance of the interaction between rifampin and verapamil in six volunteers who received single doses of verapamil, 10 mg intravenously (IV), then 120 mg orally two days later. Subjects were then given rifampin, 600 mg orally every day for 15 days. After 13 and 15 days of rifampin therapy, the IV and oral doses of verapamil were repeated. Electrocardiograms (ECG) were done and serum verapamil and norverapamil concentrations measured before and for 12 h after each dose. For IV verapamil, there was a small decrease in area under the serum concentration-time curve and an increase in clearance after rifampin therapy (p less than 0.05). There were no changes in elimination half-life, volume of distribution, or AUC for percentage of change in P-R interval-time curve (AUCPR). For oral verapamil, there were marked decreases in peak concentration, AUC, oral bioavailability (all p less than 0.005), and AUCPR (p less than 0.001) after rifampin treatment. There were no changes in time to peak concentration or elimination half-life. For oral verapamil, significant P-R interval prolongation occurred only before treatment with rifampin. The decrease in oral bioavailability and the abolition of ECG response confirm that a highly significant drug interaction exists between rifampin and verapamil given orally but not intravenously.

Verapamil-induced natriuretic and diuretic effects: dependency on sodium intake.

The influence of dietary sodium on the antihypertensive effects of verapamil and on components of sodium, water, and calcium metabolism was studied in nine white patients 50 to 65 years old with normal renin hypertension. Diets consisting of 109 and 259 mEq Na were given for 5 days each before the study drug was given. On days 4 and 9, intravenous verapamil (0.075 mg/kg) and oral verapamil (80 mg) were given, followed by 80 mg at 8-hour intervals for three doses. On days 1, 4, 5, 9, and 10, serum and urine electrolytes, osmolality (urine [Uosm], serum [Sosm], and osmolar clearance [Cosm]), calcium plasma renin activity (PRA), and levels of serum aldosterone, 1,25-hydroxyvitamin D, serum ionized calcium, parathyroid hormone, atrial natriuretic hormone (atriopeptin), and erythrocyte calcium and electrolytes were measured. On days 5 and 10, serial plasma samples for measurement of verapamil and norverapamil levels were drawn immediately after the last oral dose of verapamil. After verapamil, Uosm and Cosm decreased during both 109 and 259 mEq sodium diets (Uosm, p less than 0.025; Cosm, p less than 0.01 and p less than 0.025, respectively), but free water clearance increased during each diet (p less than 0.01). Urine volume and sodium excretion increased with the 259 mEq sodium diet (p less than 0.025 and p less than 0.01, respectively). There were no significant changes in measured values of components of calcium metabolism with either diet or after verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral verapamil and calcium infusion in patients with sick sinus syndrome.

Electrophysiologic and circulatory effects of a single oral dose of verapamil (120 mg) were evaluated in 8 patients with symptomatic sick sinus syndrome. Ninety min. after verapamil, calcium gluconate (1375 mg) was infused in an attempt to reverse the depressor actions of the drug. Verapamil significantly increased sinus node recovery time (P less than 0.05) and atrioventricular conduction time (P less than 0.01), and decreased both systolic (P less than 0.01) and diastolic blood pressure (P less than 0.05) and spontaneous heart rate (P less than 0.01). Intravenous calcium significantly reversed blood pressure reduction (P less than 0.001) and further lowered heart rate (P less than 0.05) without affecting sinus node recovery time and atrioventricular conduction significantly. There was no significant correlation between plasma verapamil concentrations and any of the cardiovascular parameters. These data confirm that verapamil is principly contraindicated in patients with sinus node dysfunction and demonstrate that the actual calcium dose, although partly reversing blood pressure reduction, cannot reverse the depressant action of the drug on the sinus and atrioventricular node in such patients.

Left ventricular function after a single large dose of verapamil

The effects of a single large dose of verapamil on left ventricular (LV) function were evaluated noninvasively in 18 chronically hypertensive patients. Each patient was given a single oral dose of verapamil, 240 mg, before and after which arterial blood pressure was measured and an echocardiogram and a phonomechanocardiogram were obtained. Reactional symmetrical myocardial hypertrophy was seen in all patients on the first echocardiogram. Results showed that heart rate was not significantly altered, but there were significant decreases (p < 0.01) in systolic blood pressure (183.89 to 127.56 mm Hg) and diastolic blood pressure (101.11 to 77.67 mm Hg). The following parameters were also significantly decreased (p < 0.01): LV ejection time (294.56 to 274.22 ms), LV diastolic diameter (45.78 to 43.99 mm), percentage change in LV diameter (33 to 27.83%), mean velocity of circumferential fiber shortening (1.12 to 1.02 circ/s), posterior wall contraction velocity (40.83 to 36.28 mm/s), LV end-diastolic volume (97.78 to 86.89 cm 3), ejection fraction (0.70 to 0.62), stroke volume (70 to 55 cm 3) and cardiac output (4.7 to 4 liters/m). Three parameters were significantly increased (p < 0.01): preejection period (104.06 to 112.06 ms), preejection period: LV ejection time ratio (0.35 to 0.41) and end-systolic volume (29.28 to 32.33 cm 3). It is concluded that a single oral dose of verapamil, 240 mg, is highly efficient in lowering arterial blood pressure in chronically hypertensive patients and in reducing the peripheral resistance and LV performance indexes.

376 AGE-DEPENDENT VERAPAMIL KINETICS AFFECT PEDIATRIC ORAL DOSE REQUIREMENTS

Although intravenous verapamil effectively terminates supraventricular tachycardia (SVT) in children, its utility as a chronic oral antidysrhythmic drug has been disappointing. To assess whether drug kinetics contribute to this problem, we measured serum concentrations before and for 24 hours after a maintenance oral dose of verapamil (mean dose 1.36 mg/kg, range 0.4-2.9 mg/kg) in 7 children with a median age of 10.8 yrs (range 2.8-15.3 yrs). All had SVT controlled by chronic oral verapamil at mean serum peak and trough concentrations of 248±117 and 64±38 ng/ml, respectively. We found several clearly age-dependent kinetic parameters: younger children demonstrated faster drug uptake “Tmax” (p <.005), lower relative bioavailability “F” (p<.01), smaller volume of distribution “Vd” (p <.005) and slower elimination half-life “t ½ β” (p <.001). Younger children also exhibited a possible diurnal variation in drug kinetics. There was no significant age-relationship in distribution half-life “t½α” or drug clearance rate. Although these changes have opposing effects on serum concentrations, their net effect in young children is for a greater dosage requirement, and perhaps a shorter dosage interval, than are currently recommended. *Supported in part by G.D. Searle & Co. of Canada, Ltd., and the Ontario Heart and Stroke Foundation.

Elevation of intraocular pressure by calcium channel blockers.

Topical administration of three different calcium channel blockers (verapamil hydrochloride, diltiazem hydrochloride, or nifedipine) increased intraocular pressure transiently in rabbits. Outflow facility and episcleral venous pressure were unchanged. Aqueous humor flow seemed to be increased 30 minutes after topical application of verapamil when estimated by the Goldmann equation or by changes in anterior chamber fluorescein-labeled dextran concentration. However, aqueous humor ascorbate concentrations and turnover of radioactive iodide did not differ from that in the untreated eye. Ocular blood volume was found to be increased after topical application of verapamil, which suggested vascular changes as a possible mechanism for the induced increase in IOP. Topical verapamil raised IOP in healthy human volunteers, but the elevation was less than observed in rabbits. Single oral doses of verapamil in rabbits or human beings had no effect on IOP.

Acute Intoxication with Verapamil

A healthy 18-year-old man was admitted to our unit two hours after a suicidal ingestion of 2 gm of verapamil. There was mild hypotension, depression of the sinus node, atrioventricular dissociation, changes of repolarization, and first-degree intranodal atrioventricular block (the His bundle electrogram revealed an atrio-His [A-H] interval of 155 msec). Twenty-four hours after ingestion, the patient was well, and the electrocardiogram was completely normal. This case gave us a good opporturnity to study the electrocardiologic effects of a huge oral dose of verapamil on a healthy young heart.