Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8.
Metabolites: The main metabolite is norverapamil which has an elimination half-life very similar to that of the parent compound, ranging from 4 to 8 hours. Verapamil undergoes an extensive hepatic metabolism. Due to a large hepatic first-pass effect, bioavailability does not exceed 20 - 35% in normal subjects. Twelve metabolites have been described. The main metabolite is norverapamil and the others are various N- and 0-dealkylated metabolites. Elimination by route of exposure: Kidney: About 70% of the administered dose is excreted in urine within 5 days as metabolites, of which 3-4% is excreted as unchanged drug. Feces: About 16% of the ingested dose is excreted within 5 days in feces as metabolites. Breast milk: Verapamil may appear in breast milk.
Verapamil yields in the dog: 5-(3,4-dimethoxyphenethylamino)-2 -(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile; 2-(3,4-dimethoxyphenyl)-5 -(n-(4-hydroxy-3-methoxyphenethyl)methylamino)-2-isopropylvaleronitrile, and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-methylaminovaleronitrile. The latter was also found in rats. /From table/ /salt not specified/
Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240 mg once daily). The predicted accumulation ratio was about 1.3-1.5 fold, which was close to the observed data of 1.4-2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug-drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.
The biotransformation pathway of verapamil, a widely prescribed calcium channel blocker, was investigated by electrochemistry (EC) coupled online to liquid chromatography (LC) and electrospray mass spectrometry (ESI-MS). Mimicry of the oxidative phase I metabolism was achieved in a simple amperometric thin-layer cell equipped with a boron-doped diamond (BDD) working electrode. Structures of the electrochemically generated metabolites were elucidated on the basis of accurate mass data and additional MS/MS experiments. We were able to demonstrate that all of the most important metabolic products of the calcium antagonist including norverapamil (formed by N-demethylation) can easily be simulated using this purely instrumental technique. Furthermore, newly reported metabolic reaction products like carbinolamines or imine methides become accessible. The results obtained by EC were compared with conventional in vitro studies by conducting incubations with rat as well as human liver microsomes (RLMs, HLMs). Both methods showed good agreement with the data from EC/LC/MS. Thus, it can be noted that EC is very well-suited for the simulation of the oxidative metabolism of verapamil. In summary, this study confirms that EC/LC/MS can be a powerful tool in drug discovery and development when applied complementary to established in vitro or in vivo approaches.
IDENTIFICATION AND USE: Verapamil is the drug of choice for prevention and treatment of paroxysmal supraventricular tachycardia. Verapamil has been shown to be effective in the treatment of angina pectoris. Verapamil may be used as an alternative treatment for mild or moderate hypertension. HUMAN STUDIES: Verapamil has a vasodilating action on the vascular system. Toxic effects occur usually after a delay of 1 to 5 hours following ingestion. After IV injection, symptoms appear after a few minutes. The main cardiovascular symptoms are: bradycardia and atrioventricular block (in 82% of cases) hypotension and cardiogenic shock (in 78% of cases) cardiac arrest (in 18% of cases). Pulmonary edema may occur. Impairment of consciousness and seizures may occur and are related to a low cardiac output. Nausea and vomiting may be observed. Metabolic acidosis due to shock and hyperglycemia may occur. Verapamil is a calcium channel blocker and inhibits the entry of calcium through calcium channels into cardiovascular cells. Verapamil reduces the magnitude of the calcium current entry and decreases the rate of recovery of the channel. Verapamil decreases peripheral vascular and coronary resistance but it is a less potent vasodilator than nifedipine. In contrast, its cardiac effects are more prominent than those of nifedipine. At doses necessary to produce arterial vasodilatation, verapamil has much greater negative chronotropic, dromotropic and inotropic effects than nifedipine. At toxic doses, calcium channel inhibition by verapamil results in three principal effects: hypotension due to arterial vasodilatation, cardiogenic shock secondary to a negative inotropic effect, bradycardia and atrio-ventricular block. The therapeutic effects of verapamil on hypertension and angina pectoris are due to arterial systemic and coronary vasodilatation. The antiarrhythmic activity of verapamil is due to a delay in impulse transmission through the AV node by a direct action. Toxicity may occur after ingestion of 1 g. Verapamil was tested on human peripheral lymphocytes in vitro using micronucleus (MN) test. The MN frequencies showed increase after all treatment. The results of FISH analysis suggest that verapamil, separately or combined with ritodrine, shows to a larger extent aneugenic than clastogenic effect. ANIMAL STUDIES: Verapamil promotes atrial fibrillation in normal dogs. In swine, verapamil toxicity, as defined by a mean arterial pressure of 45% of baseline, was produced following an average verapamil infusion dose of 0.6 +/- 0.12 mg/kg. This dose produced an average plasma verapamil concentration of 728.1 +/- 155.4 ug/L. Hypertonic sodium bicarbonate reversed the hypotension and cardiac output depression of severe verapamil toxicity in a swine model. ECOTOXICITY STUDIES: Effects of long-term exposure of verapamil on mutagenic, hematological parameters and activities of the oxidative enzymes of Nile tilapia, Oreochromis niloticus were investigated for 60 days exposure at the concentrations of 0.29, 0.58 and 1.15 mg/L in the fish liver. The exposure resulted in significantly high micronuclei induction of peripheral blood cells. The indices of oxidative stress biomarkers (lipid peroxidation and carbonyl protein) showed elevated level. There was increase in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST). In other experiments, exposure to sub-lethal concentrations of verapamil (0.14, 0.29 and 0.57 mg/L) for period of 15, 30, 45 and 60 days, led to inhibition of acetylcholinesterase activities in the brain and muscle of the fish. Transcription of catalase (CAT), superoxide dismutase (SOD) and heat shock proteins 70 (hsp70) were up-regulated in both the tissues after the study period. In Carassius auratus, the behavioral alterations were observed in the form of respiratory difficulty and loss of body balance confirming the cardiovascular toxicity caused by verapamil at higher doses. In addition to affecting the cardiovascular system, verapamil also showed effects on the nervous system in the form of altered expression of parvalbumin. Acute exposure to verapamil significantly reduced the heart rate in the embryos and larvae of common carp (Cyprinus carpio). In the D. magna chronic toxicity test, several parameters, such as the survival percentage, the body length of D. magna, the time of first reproduction, and the number of offspring per female, were adversely affected during the exposure to 4.2 mg/L verapamil. During the 24-hr short-term exposure, verapamil caused a downregulated expression of the CYP4 and CYP314 genes. During the 21-day long-term exposure, verapamil significantly reduced the expression level of the Vtg gene, a biomarker of the reproduction ability in an oviparous animal.
Verapamil inhibits voltage-dependent calcium channels. Specifically, its effect on L-type calcium channels in the heart causes a reduction in ionotropy and chronotropy, thuis reducing heart rate and blood pressure. Verapamil's mechanism of effect in cluster headache is thought to be linked to its calcium-channel blocker effect, but which channel subtypes are involved is presently not known.
Chronic therapy with verapamil is associated with a low rate of serum aminotransferase elevations that are usually mild and may resolve even with continuation of therapy. Clinically apparent liver injury with jaundice or symptoms from verapamil is uncommon and usually presents with fatigue, weakness with or without jaundice 2 to 8 weeks after starting the drug. The pattern of injury is usually mixed or cholestatic. Acute presentation can include fever, rash, arthralgias and eosinophilia, but these immunoallergic features are rarely prominent. Rapid recurrence with rechallenge has been reported. Autoantibodies are usually not present. Most cases have been mild and self-limited. Recovery is prompt with stopping verapamil and no cases of chronic hepatitis or vanishing bile duct syndrome have been attributed to its use. At least a dozen instances of acute liver injury attributed to verapamil have been published and the nature of the reaction is probably an idiosyncratic and immunologic.
