Pharmacokinetics of verapamil and its metabolite norverapamil from a buccal drug formulation

Pharmacokinetics of verapamil and its metabolite norverapamil, from buccal drug formulation administered in a dose 20 mg in relation to conventional tablets of verapamil 40 mg, used in medical practice, was determined. Buccal formulation has previously been designed as an alternative form of dosing verapamil. Bioavailability was determined by a crossover method in 12 healthy volunteers. Drug concentration in plasma was determined by means of HPLC with a fluorescence detector. For buccal formulation the average values of C(max) and AUC(0-24 h) for verapamil were much higher than for the reference Staveran tablets and amounted to 51.28 and 320.23 ng/ml h, respectively. However, for norverapamil the corresponding values for buccal formulation were much lower than for a conventional tablet. It has been demonstrated that the proposed buccal verapamil dosing ensures different metabolism of the drug as compared to tablets. Better parameters of bioavailability of verapamil from buccal formulation of twice a smaller dose than that in the tablet, prove that this new drug might be form more effective clinically than the conventional one.     

Influence of food on the bioavailability of a sustained-release verapamil preparation

The effects of food on the bioavailability of a sustained-release (SR) formulation of verapamil (SR-verapamil; Isoptin SR) were determined in an open, three-way single-dose study involving 12 volunteers receiving (in randomized order) the SR preparation (1 X 240 mg) either fasting or with food and a conventional formulation of verapamil (3 X 80 mg) fasting. Compared with the conventional formulation, SR-verapamil had a reduced Cmax, prolonged tmax, and unchanged t1/2, consistent with its SR formulation. The AUC was 80% of the conventional preparation. Concomitant food administration significantly prolonged the tmax of SR-verapamil from 7.3 +/- 3.4 to 11.7 +/- 6.3 h, but had little effect on Cmax, t1/2, or AUC. Similar results were obtained with the metabolite, norverapamil. Food administration also had little effect on the blood pressure and ECG effects of SR-verapamil. Cautions regarding taking this preparation with food therefore appear to be unnecessary.     

Verapamil and norverapamil in plasma and breast milk during breast feeding

Summary The concentrations of verapamil and norverapamil have been measured in milk and plasma samples from a 32year-old woman treated with verapamil 80 mg tds while breast-feeding her child.The average steady-state concentrations of verapamil and norverapamil in milk were, respectively, 60% and 16% of the concentrations in plasma.The breast-fed child received less than 0.01% of the dose of verapamil given to the mother. No verapamil or norverapamil (<1 ng/ml) could be detected in the plasma from the child.     

Multiple dose comparison of a whole 240 mg verapamil sustained-release tablet with two half tablets

Twelve healthy male volunteers were studied in a balanced crossover comparison of an intact 240 mg verapamil sustained-release tablet (Securon SR, Isoptin Forte Retard) given once daily for 7 days, and the same dose given as two half tablets. One subject was withdrawn because of asymptomatic second degree heart block on day 3 of verapamil treatment. The mean Cmax after dosing with whole tablets, 143 (95 per cent confidence limits 91.6-223) ng ml-1 was lower than after dosing with half tablets, 160 (107-241) ng ml-1, but this was not significant (p = 0.49). The mean steady-state Cmin values after whole and half tablets were also similar: 22.2 (12.6-39.4) ng ml-1 and 22.0 (16.2-29.9) ng ml-1, respectively (p = 0.96). The mean (+/- S.D.) tmax, AUC0-24 and t 1/2 were not significantly different: whole tablet 3.5 +/- 1.2 h, 1733 +/- 1125 ng.h ml-1 and 10.5 +/- 3.4 h, respectively, and half tablets 3.6 +/- 1.0 h, 1780 +/- 1057 ng.h ml-1 and 9.6 +/- 2.3 h, respectively. The findings for plasma norverapamil were generally similar to those for the parent drug. This investigation indicates that the formulation is sufficiently robust to retain its sustained-release properties when the tablet is halved.     

Plasma levels and urinary excretion of verapamil, norverapamil, N-dealkylverapamil (D617), N-dealkylnorverapamil (D620) following oral administration of a slow-release preparation

The kinetics of verapamil and of its N-dealkylated metabolites (norverapamil, D617, D620) were studied in six cardiac patients with normal cardiac indexes after 120 mg oral administration of the drug both as conventional preparation and as slow-release preparation. Following a dose of the slow-release preparation, the drug concentration curves were smoother and the mean bioavailability was lower in comparison with the conventional preparation. A patient taking inducing agents (phenobarbital and phenytoin) exhibited a strikingly low bioavailability. Following administration of the conventional preparation, the mean plasma half-lives of verapamil, norverapamil, D617 and D620 were 4.4, 6.6, 8.5, and 15.8 h respectively and the drug concentrations showed a triexponential decay. Urinary excretion data indicate that a saturation phenomenon may occur at level of renal tubular transport and that a competition may be suspected between D620 and the other compounds. It is concluded that various mechanisms, i.e. changes in hepatic and renal clearances, occurrence of a deep compartment, and the properties of the pharmaceutical preparation may affect verapamil kinetics during long-term treatment.     

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).     

Systemic availability of oral verapamil and effect on PR interval in man.

1 The plasma levels of verapamil and its major metabolite norverapamil were related to its effect as a Ca-antagonist on atrio-ventricular (AV) conduction, judged from prolongation of the PR interval in six normal volunteers. 2 Intravenous administration (0.1 mg kg-1) was compared to oral administration (120 mg) in each subject. 3 Intravenous verapamil showed a mean distribution half-life (alpha) of 8.5 min and elimination half-life (beta) of 2.0 h. The volume of distribution was about 112.1. Oral dosage gave an elimination half-life of 2.7 h, and a norverapamil half-life which averaged 4.6 h. The bioavailability of the oral dose averaged 22% (17 to 29%). 4 After the oral dose the percentage change in PR interval in the five appropriate subjects correlated significantly with the log plasma verapamil level (r = 0.732), but not with the log plasma norverapamil level (r = 0.078); norverapamil could not be detected after the intravenous dose. One subject developed Wenckebach type second degree AV block after each dose.     

Long-term persistence of antianginal effect of oral verapamil in chronic stable angina

The long-term antianginal effect of orally administered verapamil over 1 year of continuous treatment was assessed in 11 patients with effort-induced angina. In the short-term phase of the study, patients were given, in random order, placebo and verapamil (360 mg/day). The tolerated work load during a bicycle exercise test was 531.8 +/- 123.0 kg/min on placebo and 763.6 +/- 124.7 kg/min on verapamil (p less than 0.001). Subsequently all patients entered a long-term study of 1-year continuous treatment with 120 mg t.i.d. verapamil. The tolerated work load at 8-week (736.4 +/- 105.1 kg/min) and 1-year (804.6 +/- 101.1 kg/min) tests did not significantly differ from the results in the short-term study. The average verapamil plasma level was 138.5 +/- 90.6 ng/ml before and 357.8 +/- 199.2 ng/ml 90 min after drug administration; the average norverapamil plasma levels were, respectively, 248.0 +/- 84.4 and 368.0 +/- 135.9 ng/ml. There was no correlation between verapamil or norverapamil plasma concentrations and the antianginal effect. No patient developed signs of heart failure during the treatment. Two patients had mild constipation. The average P-R interval was slightly, although significantly (p less than 0.01) prolonged, but no patient developed first-degree atrioventricular block. We conclude that verapamil proves an effective and safe drug in the treatment of effort-induced angina; the beneficial effects of the short-term treatment are sustained during 1 year of continuous treatment.     

A validated method for the determination of verapamil and norverapamil in human plasma

The aim of the study was to develop a simple and sensitive analytical method to determine verapamil (V) and its metabolite norverapamil (N) in human plasma with use of an HPLC isocratic system with fluorescence detection, following fast extraction of the investigated compounds. Extraction recovery was 92.12% and 89.58% for V and N, respectively. Internal standard in HPLC was propranolol. Its recovery was 82.50% on the average. Limit of detection was 0.924 ng/ml and limit of determination was 3,080 ng/ml for V, what corresponds concentration in plasma 1.232 ng/ml. For N limit of detection was 0.030 ng/ml and limit of determination was 1.001 ng/ml what corresponds 0,4 ng/ml in plasma. Parameters of validation prove that precision of the presented method is very good. The method is fast and one chromatogram separation lasts about 8 minutes. 30-40 manual (without autosampler) analyses per day were done. It was used successfully in pharmacokinetic and bioavailability studies of verapamil administration in drug formulations alternative to tablets: buccal and flotation ones.     

Pharmacokinetics of verapamil in patients with hypertension

Summary Twelve hypertensive patients (WHO Stage I-II) were given oral verapamil (Isoptin) b.d. or t.d.s. as long-term treatment. The pharmacokinetics of verapamil and norverapamil were studied both after single and b.d. and t.d.s. doses of verapamil 240, 360 or 480 mg daily adjusted according to the blood pressure response. The apparent oral clearance of verapamil was decreased after both the twice and thrice daily dosage regimens (1.38 and 1.841/min, respectively) as compared to the single dose (4.39 l/min). The plasma half-life of verapamil was increased from 3.34 h (single dose) to 4.65 h (b.i.d.). Decreased elimination of norverapamil was also found after multiple doses of verapamil, as shown by an increase in the adjusted AUC of norverapamil (adjusted to a verapamil dose of 80 mg), namely from 574.9 h·ng·ml^–1 (single dose) to 1172 h·ng·ml^–1 (b.d.) and to 841 h·ng·ml^–1 (t.d.s.). The plasma half-life of norverapamil increase from 5.68 h to 7.34 h during twice daily dosing. During thrice daily verapamil, no increase in plasma half-life was found either for verapamil or norverapamil, probably due to the relatively short sampling time (6 h). The plasma concentration of verapamil and the reduction in supine systolic and diastolic blood pressure were correlated. The mean decrease in supine systolic blood pressure was 5.8 mm Hg per 100 ng verapamil/ml plasma, and for diastolic pressure 2.9 mm Hg per 100 ng verapamil/ml plasma. The mean steadystate plasma concentrations of verapamil were similar after twice and thrice daily dosing regimens, which agrees with the clinical observation that blood pressure control in hypertensive patients is as good after verapamil b.d. and t.d.s.     

An investigation of the cause of accumulation of verapamil during regular dosing in patients.

The accumulation of verapamil during regular dosing conditions was studied. Plasma concentrations of verapamil (V) and norverapamil (NV) were measured as were urinary concentrations of verapamil, norverapamil, and four other N- and O-dealkylated metabolites in nine patients after an initial single dose and after chronic oral verapamil administration to steady-state plasma concentrations. Indocyanine green (ICG) clearance was determined immediately prior to the initial verapamil dose and prior to the verapamil washout from regular dosing. An approximately two-fold accumulation of V had occurred during regular dosing. The area under the plasma concentration-time curve (AUC1) after the first dose was 417.4 +/- 276.7 ng ml-1 h (mean +/- s.d.) and increased to 786.5 +/- 54 ng ml-1 h (P less than 0.01) during one dosage interval at steady-state (AUCss). NV also tended to accumulate from an AUC1 of 552.6 +/- 411 to an AUCss 668.7 +/- 332 ng ml-1 h (P less than 0.09). The ratio of AUC-V to AUC-NV was unchanged. The verapamil elimination half-life (t 1/2) increased from 8.4 +/- 4.2 to 12.0 +/- 3.6 h (P less than 0.01) whereas the norverapamil t 1/2 was unchanged. ICG clearance was unchanged. Urinary excretion of NV increased slightly but the ratio of urinary V/NV concentrations was not significantly altered nor was the ratio of four other metabolites to verapamil or the ratio of the combined o-demethylated to the N-dealkylated metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Verapamil metabolite exposure in older and younger men during steady-state oral verapamil administration.

To determine the effect of age on exposure to the circulating major verapamil metabolites norverapamil, N-dealkylverapamil (D-617), and N-dealkylnorverapamil (D-620), plasma concentrations of verapamil and the three metabolites were determined during the last dose interval of a 14-day administration period of 240 mg of sustained release verapamil once daily in 11 older (aged 65-75 years) and 8 younger (20-28 years) healthy male volunteers. Area under the plasma concentration time curve (AUC) was greater for verapamil (mean +/- S. D.) (2815 +/- 733 older versus 1639 +/- 466 ng/ml.h(-1) young; P <. 0007) and norverapamil (2927 +/- 655 versus 2143 +/- 471 ng/ml. h(-1); P <.007); however, it was not significantly different for D-617 [2386 +/- 772 versus 1894 +/- 418 ng/ml.h(-1); not significantly different (NS)] and N-dealkylnorverapamil (897 +/- 366 versus 757 +/- 104 ng/ml.h(-1); NS) in older as compared with young subjects. These data indicate that impaired verapamil oral clearance previously described in older men does not result in decreased exposure to the formed major metabolites, rather there is increased exposure to norverapamil and the same or a trend toward greater exposure to D-617 as well. This suggests that in addition to the impaired clearance mechanisms for verapamil, which are thought to be primarily mediated by CYP3A, biotransformation processes distal to the formation of norverapamil and D-617 are impaired as well.     

Bioavailability and pharmacokinetics of ketanserin in elderly subjects

Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation.The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution.Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h.For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol.Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.     

Pharmacokinetics of verapamil and norverapamil in patients with hypertension: a comparison of oral conventional and sustained release formulations

A double blind, double dummy, randomized cross-over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects.     

Pharmacokinetics of verapamil and norverapamil from controlled release floating pellets in humans.

Pharmacokinetics of verapamil (V) in a dose of 40 mg and its metabolite norverapamil (N) from the new oral drug formulation in a form of capsule filled with floating pellets was determined. Conventional 40-mg tablets used in a medical practice served as a reference. Bioavailability studies were carried out in 12 healthy volunteers including six men and six women. In an in vitro test the pellets floated on the surface of the extraction fluid for 6 h. Mean value of maximum plasma concentration (C(max)) of V for floating pellets was 28.27 ng ml(-1) and t(max) 3.75 h. The value of the area under the concentrations versus time, AUC(0-infinity) was calculated as 364.65 ng ml(-1) h, biological half-lives of the absorption and elimination (t(0.5el)) phase were 0.5 h and 10.68 h, respectively. For the reference conventional tablets those values were 33.07 ng ml(-1), 1.21 h, 224.22 ng ml(-1) h, 0.36 h and 6.17 h, respectively. The average concentration of N in plasma was similar to that of V.     

Verapamil and norverapamil determination in human plasma by gas-liquid chromatography using nitrogen-phosphorus detection: application to single-dose pharmacokinetic studies

A sensitive (to 0.5 ng/ml) and specific method for the determination of verapamil and norverapamil which utilizes gas-liquid chromatography with nitrogen-phosphorus detection is described. A basic extraction with acid back-wash and final basic reextraction is used for the preparation of plasma samples. Standard curves using alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-beta-aminoethyl]- 3,4- dimethoxyphenylacetonitrile hydrochloride (D-517) are linear for concentrations from 0.5 to 200 ng/ml for both verapamil and norverapamil. Within-day and between-day reproducibility is good with a coefficient of variation less than 10% for all concentrations. Recovery is complete for both verapamil and norverapamil. Application of the method is demonstrated by a pharmacokinetic study in a normal volunteer who received 10 mg verapamil hydrochloride by intravenous infusion.     

The pharmacokinetics of racemic verapamil in patients with impaired renal function

The pharmacokinetics of verapamil were studied in patients with renal failure who were undergoing maintenance hemodialysis and in normal subjects after an IV infusion of 10 mg and a single oral dose of 120 mg. Plasma levels of verapamil and its active metabolite, norverapamil, were analyzed by a sensitive and specific HPLC procedure. Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose. The terminal elimination rate constant, clearance, volume of distribution, and bioavailability of verapamil were not significantly different between the two groups of subjects. In addition, the apparent maximal plasma concentration, terminal elimination rate constant, and area under the curve for norverapamil were similar in patients with renal failure and normal subjects. The study showed that the plasma disposition of verapamil and norverapamil was not affected in patients with impaired renal function. Furthermore, this study does not indicate that any change in dosage is necessary when single doses of verapamil are administered to patients with renal failure.     

Bioavailability study of two different verapamil formulations.

Relative bioavailability and bioequivalence of two oral verapamil preparations were investigated (dosage 80 mg, film-coated tablets as reference, dragées as test formulation). The clinical study was performed in a 2-period-cross-over design with 16 male healthy volunteers (mean age 28.8 +/- 3 years). The active metabolite norverapamil was included in the investigation. To assess bioequivalence several pharmacokinetic characteristics (i.e. AUC(o-oo), Cmax, tmax) were taken into account. Shortest 90% confidence intervals were calculated based on parametric (ANOVA, ANOVAlog) and non-parametric (Wilcoxon, Mann-Whitney) statistical tests. A positive decision for bioequivalence was accepted if the confidence intervals did not exceed the limits of 80-120% for AUC and 70-130% for Cmax. A mean relative bioavailability of 127% for the test preparation was found. Thus, bioavailability of the dragées is marked higher than bioavailability of the film-coated tablets.     

Effects of naringin on the pharmacokinetics of verapamil and one of its metabolites, norverapamil, in rabbits

It was reported that verapamil is metabolized via hepatic microsomal cytochrome P450 (CYP) 3A4 and that naringin (a component of grapefruit juice) inhibits CYP3A4 in humans. Hence, after oral administration of verapamil, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of verapamil and the AUC(verapamil)/AUC(D-617 (a metabolite of verapamil)) ratio were significantly greater after oral grapefruit juice in humans. The aim of this study was to determine whether similar results could be obtained from rabbits. The pharmacokinetics of verapamil and one of its metabolites, norverapamil, were investigated after oral administration of verapamil at a dose of 9 mg/kg without or with oral naringin at a dose of 7.5 mg/kg in rabbits. With naringin, the AUC of verapamil was significantly greater (28.4 versus 18.4 microg min/ml). Although, the AUC values of norverapamil were not significantly different between groups without and with naringin, the AUC(verapamil)/AUC(norverapamil) ratio was considerably greater (1.49 versus 1.11) with naringin. The above data suggested that the metabolism of verapamil and the formation of norverapamil was inhibited by naringin possibly by inhibition of CYP3A in rabbits.     

Activity and pharmacokinetics of a new oral dosage form of soluble ibuprofen.

The pharmacokinetics and the relative bioavailability of a soluble granular form (sachets) of a pharmaceutical formulation containing ibuprofen (CAS 15687-27-1) and 1-arginine were investigated in healthy volunteers. Two granular dosage forms were evaluated, 200 and 400 mg, in comparison with the commercial equivalents (tablets). After the oral administration of both granular dosage forms, a quicker absorption and a significantly higher plasma bioavailability of ibuprofen in the first hour following the treatment than after tablets administration were observed. The mean values of peak plasma concentration (microgram/ml) were 26.1 and 56.4 after treatment with 200 and 400 mg sachets respectively vs. 16.3 and 43.0 after treatment with 200 and 400 mg tablets. The mean values of peak time were 16.9 and 24.4 min after treatment with 200 and 400 mg sachets respectively vs. 90.0 and 63.7 min after treatment with 200 and 400 mg tablets. The shortening in the absorption time and the increase in the plasma concentrations did not involve a quicker drug elimination nor cause any changes in the bioavailability (mean values of the relative bioavailability indexes of 0.98 for 200 mg dosage form and 1.02 for the 400 mg one). The analgesic activity of soluble ibuprofen 400 mg was compared with that of ibuprofen 400 mg tablets in patients with osteo-articular pain, according to a single dose, double-blind cross-over balanced design. The results showed that the soluble granular form is able to determine an analgesic effect significantly quicker and higher than that of tablets.