Disease relevance of Noverapamil

• Plasma concentrations of verapamil and its metabolite, norverapamil, were measured in six patients with supraventricular tachycardia after the first and seventh dose of a regimen consisting of 120 mg every 8 hr by month [1].
• There was no correlation between plasma verapamil or norverapamil concentrations and toxicity [2].
• 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 [3].
• Verapamil and norverapamil trough plasma levels were measured in 22 children, aged from 15 days to 17 years, under chronic oral treatment with the drug (mean daily dose +/- SD: 4.9 +/- 1.4 mg/kg) for supraventricular tachyarrhythmias (n = 20) or hypertrophic cardiomyopathy (n = 2) [4].
• Verapamil, a calcium channel blocking vasodilator used in the treatment of angina, arrhythmias and hypertension, and norverapamil, an active metabolite, were used as model compounds in these investigations [5].

High impact information on Noverapamil

• The concentrations of verapamil and norverapamil, as well as their enantiomers, were quantified in serum by chiral HPLC [6].
• Values for the maximum rate of metabolism (V(max)) of verapamil N-dealkylation (formation of D-617) and N-demethylation (formation of norverapamil) activities correlated with the CYP3A4 protein content in both organs [7].
• Concentrations of talinolol, verapamil, and its main metabolite norverapamil were measured in serum with HPLC [8].
• Norverapamil AUC also rose from 1225 +/- 405 to 2312 +/- 963 ng/ml/hr during the attainment of steady state [1].
• Additionally, norverapamil and reserpine have, respectively, a 60- and 40-fold preference for inhibition of P-gp over CYP3A4 [9].

Biological context of Noverapamil

• Similar effects on norverapamil pharmacokinetics were observed [10].
• Enantioselective kinetics of verapamil and norverapamil in isolated perfused rat livers [11].
• In vitro, norverapamil had no effect on R- and S-verapamil protein binding up to 1000 ng ml-1 [12].
• Blood pressures, heart rates, P-R intervals; and serum concentrations of R-/S-verapamil and norverapamil were measured multiple times in patients during the last day of each therapy [13].
• There was no correlation between plasma verapamil or norverapamil concentration and blood pressure response [14].

Anatomical context of Noverapamil

• Rapid high-performance liquid chromatographic method for the measurement of verapamil and norverapamil in blood plasma or serum [15].
• The inactivation efficiency of verapamil and norverapamil was 30 times and 45 times lower, respectively, for CYP3A5-expressing microsomes compared with CYP3A5-non-expressing microsomes [16].
• Verapamil and norverapamil in plasma and breast milk during breast feeding [17].
• (+)-R, (-)-S-, racemic verapamil, norverapamil and D617 alone had no effect on cell growth in sensitive or resistant cell lines in concentrations up to 20 microM [18].
• We measured the basolateral-to-apical fluxes of the P-glycoprotein substrates digoxin and vinblastine in the presence and absence of verapamil, (R)-norverapamil, (S)-norverapamil, racemic norverapamil, PR-22, or D-620 across confluent monolayers of Madin-Darby canine kidney (MDCK) cells that express P-glycoprotein on their apical membranes [19].

Associations of Noverapamil with other chemical compounds

• Direct determination of the enantiomeric ratio of verapamil, its major metabolite norverapamil and gallopamil in plasma by chiral high-performance liquid chromatography [20].
• 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol [21].
• Plasma and intracellular doxorubicin concentrations and plasma concentrations of verapamil and norverapamil were determined with HPLC [22].
• The aim of present study is to investigate the effect of naringin on the pharmacokinetics of verapamil and its major metabolite, norverapamil in rabbits [23].

Gene context of Noverapamil

• At 50 microM, norverapamil showed time-dependent inhibition of CYP3A5 (30%), but to a much lesser extent compared with that of CYP3A4 (80%) [16].
• Specific antibodies directed against CYP3A were used to inhibit formation of D-617 and norverapamil [24].
• Vincristine binding to solutions of alpha 1-acid glycoprotein (AGP, 2 mg/ml) and the effect of D,L-verapamil, verapamil enantiomers and the verapamil metabolites norverapamil and D617 were investigated in vitro using equilibrium dialysis and 3H-labelled vincristine [25].
• Interestingly, P450 2C8 readily metabolized both S- and R-verapamil to D-617, norverapamil and PR-22 with only slightly higher Km values than noted for P450s 3A4 and 3A5 [26].
• In contrast, P450 2C8 produced both the D-620 and PR-22 metabolites from the enantiomers of norverapamil, again with stereoselective preference seen for the S-enantiomer [26].

Analytical, diagnostic and therapeutic context of Noverapamil

• Plasma verapamil and norverapamil concentrations were analyzed by high pressure liquid chromatography [27].
• Simultaneous quantitation of verapamil, norverapamil, and N-dealkylated metabolites in human plasma following oral administration [28].
• Severe renal failure requiring hemodialysis did not change the time course of verapamil and norverapamil plasma concentrations after either the IV or oral dose [3].
• Verapamil and norverapamil determination in human plasma by gas-liquid chromatography using nitrogen-phosphorus detection: application to single-dose pharmacokinetic studies [29].
• Stereoselective determination of verapamil and norverapamil by capillary electrophoresis [30].

References