The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

“…[35][36][37] For example, the calcium channelblocking agent verapamil was observed to induce transient complete heart block, congestive heart failure and severe hypotension. 38 However, cardiovascular toxicity can be distinguished from P-glycoprotein inhibition, as demonstrated with verapamil chiral enantiomers 39,40 and several other MDR-reversing drugs. 33,34 Preclinical studies performed in rats and dogs did not anticipate the prolonged cardiac repolarization observed in most patients who received cinchonine.…”

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

“…Norverapamil is known to have only 20% of the cardiovascular activity of the parent compound, when using the racemic mixture of verapamil (Neugebauer, 1978). Rverapamil has been shown to have a five-to tenfold lower cardiac activity than does the S-enantiomer (Echizen et al, 1985), and thus nor-dexverapamil can be speculated to almost lack cardiac effects. Accordingly, a nor-dexverapamil to dexverapamil ratio of > 1 may be associated with diminished cardiac toxicity, without sacrificing MDR reversing potency.…”

“…The formulation of verapamil used in those studies has been a racemic mixture of R-and S-verapamil. R-verapamil has been reported to have cardiac activity that is five-to ten-fold lower than that produced by S-verapamil (Echizen et al, 1985), whereas the two isomers have shown similar molar potency in reversing P-gp-associated MDR (Gruber et al, 1988;Pirker et al, 1990 Epirubicin was given at 120 mg m-2 as intravenous infusion over 15 min. The epirubicin dose was reduced by 25% if any of the following occurred: WBC nadir <1.0 x 109 1-'; granulocyte nadir of <0.9 x 109 1-' if associated with infection; platelet nadir of <50 x 109 1-1; mucositis of WHO grade .3; mucositis of WHO grade 2 lasting >7 days.…”

Stereoselective Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil in Rabbits.

“…In humans, the bioavailability of S-VP is about 20%, whereas that of R-VP is about 50%. [1][2][3][4] The plasma protein binding of R-VP is higher than that of S-VP (free fraction: 7% and 12%, respectively). 5,14) We recently reported that the binding of VP to a1-acid glycoprotein and phosphatidylserine showed enantioselectivity and an interaction between enantiomers.…”

“…Echizen et al reported that the antiarrhythmic effect of S-VP is 10-15 times higher than that of R-VP in humans, after administration of each enantiomer. [2][3][4] However, these studies have only compared the pharmacological effect between the VP enantiomers after their administration. It is not known whether racemic VP shows pharmacokinetic and further pharmacodynamic interactions between enantiomers.…”