Pharmacokinetics and pharmacodynamics of R- and S-gallopamil during multiple dosing.

AIMS: Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h). METHODS: Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording. RESULTS: The apparent oral clearances (R: 4.8 l min-1 (95% CI: 2.9-6.8); S: 5.5 l min-1 (95% CI: 2.5-8.5)) and half-lives (R: 6.2 h; S: 7.2 h) of R- and S-gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026-0. 045); S: 0.051 (95% CI: 0.033-0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14. 0-57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed. CONCLUSIONS: The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady-state and are therefore not substantially altered compared with the single dose administration of gallopamil.

Mechanism of verapamil block of a neuronal delayed rectifier K channel: active form of the blocker and location of its binding domain.

1. The mechanism of verapamil block of the delayed rectifier K currents (I K(DR)) in chick dorsal root ganglion (DRG) neurons was investigated using the whole-cell patch clamp configuration. In particular we focused on the location of the blocking site, and the active form (neutral or charged) of verapamil using the permanently charged verapamil analogue D890. 2. Block by D890 displayed similar characteristics to that of verapamil, indicating the same state-dependent nature of block. In contrast with verapamil, D890 was effective only when applied internally, and its block was voltage dependent (136 mV/e-fold change of the on rate). Given that verapamil block is insensitive to voltage (Trequattrini et al., 1998), these observations indicate that verapamil reaches its binding site in the uncharged form, and accesses the binding domain from the cytoplasm. 3. In external K and saturating verapamil we recorded tail currents that did not decay monotonically but showed an initial increase (hook). As these currents can only be observed if verapamil unblock is significantly voltage dependent, it has been suggested (DeCoursey, 1995) that neutral drug is protonated upon binding. We tested this hypothesis by assessing the voltage dependence of the unblock rate from the hooked tail currents for verapamil and D890. 4. The voltage dependence of the off rate of D890, but not of verapamil, was well described by adopting the classical Woodhull (1973) model for ionic blockage of Na channels. The voltage dependence of verapamil off rate was consistent with a kinetic scheme where the bound drug can be protonated with rapid equilibrium, and both charged and neutral verapamil can unbind from the site, but with distinct kinetics and voltage dependencies.

Pharmacokinetics and pharmacodynamics of the enantiomers of gallopamil.

The pharmacokinetics and pharmacodynamics of the enantiomers of the calcium antagonist gallopamil have been investigated in six healthy volunteers. Each subject was studied on five occasions after receiving, in randomized order: placebo, 25 mg of (R)-gallopamil, 25 mg of (S)-gallopamil, 50 mg of pseudoracemic [25 mg of deuterated (S)-gallopamil and 25 mg of (R)-gallopamil] and 100 mg of (R)-gallopamil HCl orally. After separate administration, the apparent oral clearances of both enantiomers were similar [(R), 15.1 +/- 9.9 liters/min; (S), 11.0 +/- 6.0 liters/min], indicating that gallopamil first-pass metabolism is not stereoselective. After coadministration, the apparent oral clearance of each enantiomers decreased [(R), 5.9 +/- 2.8 liters/min; (S), 5.8 +/- 2.66 liters/min], suggesting that a partial saturation of first-pass metabolism occurs because the dose was twice as high than for the single enantiomers. Serum protein binding and renal elimination of gallopamil are stereoselective, favoring (S)-gallopamil. Analysis of urine samples revealed a marked degree of stereoselectivity in the formation of O- and N-dealkyl metabolites. Because these showed opposite stereoselectivity, canceling out each other, the net result was no or only marginal stereoselectivity. Twenty-five milligrams of (S)-gallopamil prolonged the PR interval in all subjects; however, a greater effect was elicited by 50 mg of (RS)-gallopamil. (R)-Gallopamil (100 mg) did not significantly alter the PR interval, although higher concentrations were attained than after the pseudoracemate. Based on a consideration of (S)-gallopamil serum concentrations, a comparable relationship between (S)-gallopamil level and effect occurred after (S)- and (RS)-gallopamil, indicating that the pharmacological effect produced by the racemate could be totally accounted for by the higher concentrations of (S)-gallopamil attained.

Efficacy and pharmacokinetics of gallopamil in patients with coronary artery disease.

We prospectively studied 10 patients with stable exertional ischaemia, selected from a larger group of patients referred for suspected coronary artery disease or to detect residual ischaemia after myocardial infarction, to evaluate pharmacokinetic changes during chronic treatment with gallopamil and its correlation with clinical efficacy in patients with coronary artery disease. Our study consisted of a 1-week run-in single-blind placebo treatment and a 4-week single-blind gallopamil treatment. At the end of the run-in period patients underwent two different exercise tests, the first 2 hours and the second 7 hours after placebo administration. During active treatment all patients underwent two different exercise tests, the first 2 hours and the second 7 hours after gallopamil (50 mg) administration on the 1st and 28th days of gallopamil therapy. On the same days in eight of the patients we evaluated gallopamil pharmacokinetic changes. Our data revealed a rapid increase of unchanged gallopamil and its metabolite (norgallopamil) in the plasma, and a peak concentration of these substances about 2 hour after oral administration on both the 1st and 28th day of observation. Moreover, our results demonstrated an increase between the first and 28th day of treatment in peak concentration of unchanged gallopamil in the plasma, and of AUC 0-infinity and AUC o-c values during chronic treatment with gallopamil. Our clinical data showed an improvement in exercise results during gallopamil therapy related to increased concentration of the drug.

Interaction between gallopamil and cardiac ryanodine receptors.

1. In a sarcoplasmic reticulum fraction obtained from rat hearts, the analysis of equilibrium [3H]-ryanodine binding showed high and low affinity sites (KD = 1.3 nM and 2.8 microM, Bmax = 2.2 pmol mg-1 and 27.8 pmol mg-1). The dissociation rate constant increased at 1 microM vs 4 nM [3H]-ryanodine concentration, and micromolar ryanodine slowed the dissociation of nanomolar ryanodine. 2. The binding of 4 nM [3H]-ryanodine was not affected by gallopamil, while the binding of 100 nM to 18 microM [3H]-ryanodine was partly displaced. Data analysis suggested that gallopamil inhibited low affinity [3H]-ryanodine binding, with IC50 in the micromolar range. 3. Gallopamil decreased the dissociation rate constant of 1 microM [3H]-ryanodine. While gallopamil alone did not affect the dissociation of 4 nM [3H]-ryanodine, gallopamil and micromolar ryanodine slowed it to a greater extent than micromolar ryanodine alone. 4. Our results are consistent with the hypothesis that the ryanodine receptor is a negatively cooperative oligomer, which undergoes a sequential alteration after ryanodine binding. Gallopamil has complex actions: it inhibits ryanodine binding to its low affinity site(s), and probably modulates the cooperativity of ryanodine binding and/or the transition to a receptor state characterized by slow ryanodine dissociation. These molecular actions could account for the previously reported effect of gallopamil on the sarcoplasmic reticulum calcium release channel.

Gallopamil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in ischaemic heart disease.

Gallopamil is a methoxy derivative of verapamil. As is typical of the phenylalkylamine class of calcium antagonists, it acts on the vascular system, and on the heart and its nodal structures. In the treatment of stable angina pectoris, gallopamil is at least as effective as nifedipine and diltiazem, though apparently better tolerated than nifedipine. Typical of calcium antagonists there is little or no tolerance to the antiischaemic effects of gallopamil. Preliminary studies indicate that gallopamil, like other calcium antagonists, has cardioprotective potential. However, further investigation is required to explore the clinical relevance of the improved myocardial regional perfusion and free fatty acid utilisation in reversibly ischaemic regions, and the potential of delayed ischaemia during angioplasty that is observed during gallopamil administration. Gallopamil is well tolerated, exhibiting a low propensity for causing cardiovascular and gastrointestinal adverse effects, thus making it a suitable alternative to other calcium antagonists for the treatment of patients with ischaemic heart disease.

Comparison of acute and steady-state conditions of gallopamil therapy in stable angina pectoris.

We studied 12 patients with stable effort angina in a randomized, double-blind, cross-over and placebo-controlled trial to compare the different antianginal efficacy of "acute" and "chronic" (after reaching a steady-state level) gallopamil therapy. Efficacy was assessed using treadmill exercise testing (Bruce protocol) after a 50 mg single-dose and at the end of a nine-dose course of 50 mg of gallopamil (given three times a day). Three daily exercise tests were performed the first, second, fifth and eighth day of the study protocol at 8, 12 and 16 h. Four hours after a single-dose of gallopamil 50 mg both angina-free exercise time and time to 1 mm ST segment depression increased by a mean value of 78 s (p < 0.003) and 53 s (p < 0.03), respectively, with respect to placebo values. Under steady-state conditions exercise time and time to 1 mm ST segment depression increased by a mean value of 59 s (p < 0.009) and 46 s (p < 0.015), respectively, 4 h after the last dose. The duration of the anti-ischemic effects was no longer present after 8 h for both treatment schedules. Furthermore no significant differences were observed on parameters of ischemia after a single dose as compared to "chronic" therapy. The results of this study reveal that, in accordance with the pharmacodynamic properties of the drug, the anti-ischemic efficacy of 50 mg of gallopamil remains for approximately 4 h. Reaching a steady-state condition does not imply a prolongation of the anti-ischemic effect.

Red blood cell partitioning of gallopamil, verapamil and norverapamil.

In-vitro binding of calcium-antagonists gallopamil and verapamil (and its main metabolite norverapamil) to human red blood cells (RBCs) was investigated. The drugs are bound reversibly and dose dependent to RBCs in the same order of magnitude, with partition-coefficients of kRBC = 0.12-0.34 for gallopamil, kRBC = 0.10-0.30 for verapamil and kRBC = 0.10-0.27 for norverapamil. The data indicate that, although RBCs may act as subcompartments of the blood for this class of compounds, they may have no influence on therapeutic plasma concentrations, due to their low kRBC.

Determination of gallopamil in human plasma by selected ion monitoring.

A gas chromatographic mass spectrometric procedure using selected ion monitoring is described for the quantification of gallopamil in human plasma. Gas chromatographic separation of gallopamil from phenolic metabolite isomers is made possible by treatment with ethyl chloroformate. The detection limit for the quantitation by the present method is 0.09 ng/ml of plasma. The method has sufficient sensitivity to permit pharmacokinetic studies with human subjects following the oral administration of gallopamil hydrochloride.

Pathways of gallopamil metabolism. Regiochemistry and enantioselectivity of the N-dealkylation processes.

The N-dealkylation pathway for the metabolism of pseudoracemic gallopamil was studied in the presence of rat and human liver microsomes and in vivo in rats and man. Metabolites were characterized by comparison of their GC/MS retention times and fragmentation patterns with those of authentic compounds. In the presence of rat liver microsomes, N-dealkylation accounted for about 90% of the observed oxidative metabolism, affording a 4:1 ratio of norgallopamil (2) and, N-methyl-N-[2-methyl-3-cyano-3-(3,4,5-trimethoxyphenyl)-6-hexyl] amine (3), and about 1% of N-methyl-N-(3,4-dimethoxyphenethyl)amine (4). Secondary amines 2 and 3 arose enantioselectively from S-(-)-gallopamil, the S/R ratios being 1.36 and 1.71, respectively. The alcohols, 3,4-dimethoxyphenylethanol (6) and 2-methyl-3-cyano-3-(3,4,5-trimethoxyphenyl)-6-hexanol (8), were formed from the respective intermediate aldehydes 5 and 7, probably non-enzymatically, under the reductive conditions (NADPH) of the microsomal incubations. Incubation of gallopamil with 9,000g supernatant fraction of rat liver led to carboxylic acid metabolites arising from oxidative metabolism of the aldehydes. 3,4-Dimethoxyphenylacetic acid (12) and 4-(3,4,5-trimethoxyphenyl)-5-methyl-4-cyanohexanoic acid (11) were formed in a 3:5:1 ratio. In the presence of human liver microsomes, formation of 2 also predominated over formation of 3, with alcohols 6 and 8 being produced as well. However, 4 was not observed. Consistently, the N-dealkylation process provided slightly more R than S products with the S/R ratio being 0.7-0.9 for metabolites 2, 3, 6, and 8. The amines formed from N-dealkylation were also observed as urinary metabolites in a human subject after a single oral dose of pseudoracemic gallopamil.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioequivalency of three tableted gallopamil products.

A three cross-study was conducted in 12 healthy male volunteers to evaluate the relative bioavailability of three different gallopamil tablets: Product A-Galcan 25 mg, Product B-Galcan 50 mg and Product C-Procorum 50 mg. Each dose was administered as a single tablet after an overnight fast, and blood samples were obtained for 12 hours. There was no statistically significant differences among the three products for the mean area under the plasma concentration-time curves (when corrected for the different doses). The relative bioavailability of Product A and B to Product C was respectively 96.3% (ESM = 12.4%) and 103.1% (ESM = 10.2%). Statistically significant (p less than 0.05) differences were found in Tmax between Product C (1.0 hr) and both Product A (2.1 hr) and Product B (2.4 hr). A longer-lasting absorption should always diminish peak to trough fluctuations during multiple dosing and to this extent Product B has some advantage over Product C.

Metabolism of the calcium antagonist gallopamil in man.

The metabolism of gallopamil (5-[(3,4-dimethoxyphenyl)methylamino]-2-(3,4,5-trimethoxyphenyl) -2- isopropylvaleronitrile hydrochloride, Procorum, G) was studied after single administration (2 mg i.v., 50 mg p.o.) of unlabelled and labelled G (14G, 2H). TLC, HPLC, GLC, MS and RIA were used for assessment of G and its metabolites in plasma, urine and faeces. G clearance is almost completely metabolic, with only minimal excretion of unchanged drug. Metabolites represent most of the plasma radioactivity after p.o. administration. They are formed by N-dealkylation and O-demethylation with subsequent N-formylation, or glucuronidation, respectively. Compound A, derived by loss of the 3,4-dimethoxyphenethyl moiety of G is the main metabolite in plasma and urine (about 20% of the dose). This metabolite is accompanied by its N-formyl derivative (C), by the N-demethylated compound (H) and the acid (F), formed by oxidative deamination of A. Only 3 unconjugated monphenoles from several O-demthylated products showed distinct plasma levels which were nevertheless lower than metabolite A. These metabolites had no relevance to the pharmacodynamic action. Conjugated monophenolic and diphenolic products represented the major part in plasma and were excreted predominantly via the bile: they represented almost the whole faecal metabolite fraction. Less than 1% of the dose was recovered unchanged in the urine. About 50% of the dose is excreted by urine and 40% by faeces.

[Pharmacokinetics and metabolism of gallopamil]. / Pharmakokinetik und Metabolismus von Gallopamil.

Despite its almost complete absorption following oral administration, gallopamil has an absolute bioavailability of only 15% due to an extensive hepatic first-pass metabolism. During multiple oral dosing bioavailability increases to approximately 25% indicating a partial saturation of first-pass metabolism. Since the half-life time of gallopamil is on average 3-6 h a minimum of three times daily dosing of the instant-release 50 mg tablet is required in order to maintain therapeutic plasma concentrations. The sustained-release 100 mg tablet which recently became available has a relative bioavailability comparable to the instant release preparation. Due to the delayed drug liberation therapeutic plasma concentrations are maintained for 24 h following once or twice daily administration of this drug preparation.

[Effectiveness of retard gallopamil in patients with stress-induced ST-segment depression and silent myocardial ischemias]. / Wirksamkeit von Gallopamil retard bei Patienten mit belastungsinduzierter ST-Streckensenkung und stummen Myokardischämien.

At a dosage of 75 mg b.i.d., gallopamil retard represents a suitable medication for the treatment of both symptomatic and asymptomatic ischemic episodes, as could be demonstrated in patients with coronary heart disease ascertained by angiography, positive exercise testing, and more than five ischemic episodes in Holter monitoring over 48 h. The results of our study furnish proof that more than 60% of ischemic episodes recorded in patients with stable angina pectoris during Holter monitoring over 48 h, have been asymptomatic, i.e., silent. It must thus be postulated that effective antianginal therapy must be able to suppress both symptomatic and asymptomatic ischemic episodes. This should be documented by Holter monitoring over 48 h. It has not been established yet which criteria: duration of ST-segment depression, frequency of ischemic episodes, or area integral of ST-segment depression, furnish the most adequate parameters for assessment of ischemia. Assessment of the three criteria, taken together, is likely to be most reliable and should thus, in particular, be adhered to in evidencing efficacy in an antianginal drug trial.