Pharmacokinetics of (+)‐, (‐)‐ and (+/‐)‐verapamil after intravenous administration.

Eichelbaum, Michel; Mikus, Gerd; Vogelgesang, B

doi:10.1111/j.1365-2125.1984.tb02371.x

Cited by 174 publications

(63 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In humans two to three times higher verapamil plasma levels are necessary after oral intake in order to cause equieffective increases in P-R intervals of electrocardiograms as after intravenous administration (Eichelbaum et al, 1980). The cause of this difference is that the bioavailability of (-)-verapamil is smaller than that of( + )-verapamil (Eichelbaum et al, 1984) (Eichelbaum et al, 1984) and also because of a higher clearance of (-)-verapamil through the liver (Eichelbaum et al, 1981) the bioavailability of (+ )-verapamil is at least twice that of (-)-verapamil. Thus, it seems reasonable to conclude that at least 25% of the myocardial effects of orally administered racemic verapamil can be accounted for by the (+ )-enantiomer in man.…”

Section: Discussionmentioning

confidence: 96%

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart

Ferry

Glossmann

Kaumann

1985

British J Pharmacology

View full text Add to dashboard Cite

Ventricular preparations from patients with mitral disease and hypertrophic obstructive cardiomyopathy (HOCM) were set up to contract isometrically. Ventricular membrane particles were also prepared and putative calcium channels were labelled with [3H]‐nimodipine. Positive staircase was induced by varying the rate of stimulation of isolated strips from 6 min−1 to 120 min−1 in the presence of 6–60 μm (—)‐adrenaline or (—)‐noradrenaline. (—)‐Verapamil 3–5 μm or (+)‐verapamil 20–30 μm reversed the force‐frequency relationship (i.e. caused negative staircase) in preparations from patients with mitral disease or HOCM. In subendocardial strips of ventricular septum from 5 patients with HOCM paced at 60 min−1, both (—)‐verapamil and (+)‐verapamil caused cardiodepression. Half‐maximal cardiodepression was observed with 0.4 μm (—)‐verapamil and with 3 μm (+)‐verapamil. [3H]‐nimodipine bound to ventricular membrane particles in a saturable, reversible fashion to a high affinity site with an equilibrium dissociation constant of 0.23 nm. The density of these sites was 95 fmol mg−1 of membrane protein. Binding of the tritiated 1,4‐dihydropyridine was stereoselectively inhibited by 1,4‐dihydropyridine enantiomers and nifedipine. (—)‐Verapamil and (+)‐verapamil inhibited high affinity [3H]‐nimodipine binding in a negative heterotropic allosteric manner with (—)‐verapamil being 5 times more potent than (+)‐verapamil on an IC50 basis. At a given [3H]‐nimodipine concentration, (+)‐verapamil inhibited a greater fraction of specific [3H]‐nimodipine binding. The allosteric mode of (+)‐verapamil inhibition of [3H]‐nimodipine binding was confirmed by kinetic studies. (—)‐Verapamil shifted (+)‐verapamil‐binding inhibition curves to the right in an apparently competitive fashion. The inversion of staircase caused by both verapamil enantiomers suggests that they cause a use‐dependent channel blockade. The similar potency ratios for binding and for cardiodepression are indicative of a common locus of action for both verapamil enantiomers within the calcium channel.

show abstract

Section: Discussionmentioning

confidence: 96%

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart

Ferry

Glossmann

Kaumann

1985

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…There Eichelbaum et al, 1980Eichelbaum et al, , 1981Eichelbaum et al, a,b, 1984McAllister & Kirsten 1982). Previous studies have demonstrated that the same concentration of plasma verapamil following oral administration appeared to be two to three times less potent than that following i.v.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective first‐pass metabolism of highly cleared drugs: studies of the bioavailability of L‐ and D‐verapamil examined with a stable isotope technique.

Vogelgesang¹,

Echizen²,

Schmidt³

et al. 1984

Brit J Clinical Pharma

Self Cite

167

View full text Add to dashboard Cite

The pharmacokinetics of dextro(+)‐ and levo(‐)‐verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (‐)‐ and dideuterated (+)‐isomer. (+)‐verapamil exhibited approximately five times greater Cmax (+): 240 +/‐ 81.1 ng/ml, (‐): 46.1 +/‐ 15.7 ng/ml, P less than 0.0001) and AUC than (‐)‐verapamil. The apparent oral clearance (CLo) for (+)‐verapamil was significantly smaller than that for (‐)‐verapamil (+): 1.72 +/‐ 0.57 l/min, (‐): 7.46 +/‐ 2.16 l/min, P less than 0.001). The bioavailability of (+)‐verapamil (50%) was 2.5 times greater than that of (‐)‐verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first‐pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (‐): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (‐): 5.38 h, respectively. Whereas the (+)‐ to (‐)‐verapamil plasma concentration ratio following oral administration was 4.92 +/‐ 0.48, the ratio following i.v. administration was approximately 2. (‐)‐verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)‐verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (‐)‐isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.

show abstract

“…Verapamil was recently found to exhibit stereoselective plasma protein binding and hepatic metabolism in humans (Eichelbaum et al, 1984;Vogelgesang et al, 1984;Echizen et al, 1985). If the same phenomena occur in rats there is a possibility that calcium antagonist potency ratios in vivo and in vitro may be different.…”

Section: Introductionmentioning

confidence: 99%

The mechanism of action of the optical enantiomers of verapamil against ischaemia‐induced arrhythmias in the conscious rat

Curtis

Walker

1986

British J Pharmacology

View full text Add to dashboard Cite

1 The actions of(-)-verapamil (0.2-6mg kg-')and (+ )-verapamil (0.4-12mg kg-')against arrhythmias induced by coronary artery occlusion were studied in conscious rats. 2 Intravenously administered (-)-and (+ )-verapamil dose-dependently reduced ventricular arrhythmias. (-)-Verapamil was consistently 4 times more potent than (+ )-verapamil. 3 In the same animals, (-)-verapamil was approximately 4 times more potent than (+ )-verapamil for effects on heart rate and blood pressure. Both enantiomers prolonged P-R interval, but had no effect on QRS interval. 4 In separate groups of conscious rats, neither enantiomer influenced the threshold voltage and pulse width required to elicit fibrillo-flutter, or altered the maximum following frequency, during electrical stimulation of the left ventricle. 5 In isolated, paced, Langendorff-perfused ventricles of the rat, both enantiomers dose-dependently reduced contractility, (-)-verapamil being 8-21 times more potent than (+ )-verapamil; both absolute and relative potencies were dependent on potassium concentration. 6 These results are compatible with the hypothesis that calcium antagonism in the ischaemic ventricular myocardium is antiarrhythmic during acute myocardial ischaemia.

show abstract

Pharmacokinetics of (+)‐, (‐)‐ and (+/‐)‐verapamil after intravenous administration.

Cited by 174 publications

References 21 publications

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart

Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human heart

Stereoselective first‐pass metabolism of highly cleared drugs: studies of the bioavailability of L‐ and D‐verapamil examined with a stable isotope technique.

The mechanism of action of the optical enantiomers of verapamil against ischaemia‐induced arrhythmias in the conscious rat

Contact Info

Product

Resources

About