Norverapamil

Last updated
Norverapamil
Norverapamil.svg
Names
IUPAC name
(RS)-2-(3,4-Dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylamino]-2-isopropylpentanenitrile
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.060.476 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 266-544-8
PubChem CID
UNII
  • InChI=1S/C26H36N2O4/c1-19(2)26(18-27,21-9-11-23(30-4)25(17-21)32-6)13-7-14-28-15-12-20-8-10-22(29-3)24(16-20)31-5/h8-11,16-17,19,28H,7,12-15H2,1-6H3 X mark.svgN
    Key: UPKQNCPKPOLASS-UHFFFAOYSA-N X mark.svgN
  • InChI=1/C26H36N2O4/c1-19(2)26(18-27,21-9-11-23(30-4)25(17-21)32-6)13-7-14-28-15-12-20-8-10-22(29-3)24(16-20)31-5/h8-11,16-17,19,28H,7,12-15H2,1-6H3
    Key: UPKQNCPKPOLASS-UHFFFAOYAQ
  • CC(C)C(CCCNCCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC
Properties
C26H36N2O4
Molar mass 440.584 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Norverapamil is a calcium channel blocker. It is the main active metabolite of verapamil. [1] It contributes significantly to the therapeutic effects of verapamil, which include the treatment of hypertension, angina, and arrhythmias. [2] Despite being a metabolite of verapamil, norverapamil retains much of the pharmacological activity of verapamil, particularly impacting the calcium ion flow through L-type calcium channels, leading to its therapeutic cardiovascular and vasodilation effects. [3]

Contents

Pharmacodynamics

Norverapamil inhibits L-type calcium channels located in the heart and blood vessels, leading to several pharmacological effects including vasodilation, negative inotropy, and negative dromotropy. Norverapamil relaxes the smooth muscles of blood vessels, reducing systemic vascular resistance and consequently lowering blood pressure. [3] Also, by decreasing calcium influx into heart muscle cells, it is able to lower myocardial contractility. This makes it useful in reducing the workload of the heart, particularly in cardiovascular conditions such as angina. [3] Norverapamil is also able to slow atrioventricular (AV) conduction, which is useful in controlling supra-ventricular arrhythmias by controlling the heart rate through reduced electrical conduction. [2]

Pharmacokinetics

Norverapamil is a metabolite of verapamil and is primarily produced by the N-demethylation performed by the CYP3A4 enzyme in the liver. [4] Its half-life is approximately 6–9 hours, and it is eliminated primarily through renal excretion. [2] As approximately 80% of the drug is protein-bound, its distribution is significantly influenced by factors such as liver function and serum protein levels. [2]

The effects of norverapamil are dose-dependent, with higher doses producing more pronounced effects. In individuals with hepatic or renal impairments, dose adjustments are necessary to avoid potential toxicity due to its slow metabolism. [4]

Interaction with P-Glycoprotein

Norverapamil, like verapamil, interacts with P-glycoprotein (P-gp), as a calcium channel antagonist. P-gp is a membrane transporter that affects the absorption, distribution, and elimination of many drugs. [2] As a substrate, norverapamil’s absorption is influenced by P-gp, while as an inhibitor, it may affect the bioavailability of other drugs that rely on P-gp for elimination. [3] These interactions are clinically significant when used alongside other P-gp substrates, such as digoxin, increasing their blood concentrations and potentially leading to adverse effects. [5]

Factors that affect metabolism

Both sex and age have been shown to influence the metabolism of norverapamil. [6] One key observation is that women tend to produce more norverapamil than men, which may be attributed to higher CYP3A4 enzyme activity or lower P-glycoprotein activity in women. Additionally, both sex and age contribute to differeneces in the stereoselective formation of noreverapamil, which affect the drug's effectiveness. However, there is some debate about whether these variations are entirely due to sex differences or if it's simply factors like differences in lean muscle mass and size play a role in drug metabolism. [7]

Interestingly, while sex and age are important factors, food intake does not significantly affect the metabolism or activity of norverapamil. Studies suggest that meals do not alter the drug’s pharmacokinetics, meaning its activity remains consistent regardless of food consumption. [8]

Another factor that can alter the metabolism and activity of norverapamil are drugs which interact with CYP3A4 enymes and P-glycoproteins. One such example of a drug is the cholesterol medication atorvastatin which inhibits both CYP3A4 enzymes and P-Glycoproteins. [9]

References

  1. ↑ Christiane Pauli-Magnus, Oliver von Richter, Oliver Burk, Anja Ziegler, Thomas Mettang, Michel Eichelbaum and Martin F. Fromm (2000). "Characterization of the Major Metabolites of Verapamil as Substrates and Inhibitors of P-glycoprotein". Journal of Pharmacology and Experimental Therapeutics. 293 (2): 376–382. doi:10.1016/S0022-3565(24)39245-6. PMID   10773005.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. 1 2 3 4 5 Bauer, Martin; Wulkersdorfer, Beatrix; Karch, Rudolf; Philippe, Cécile; Jäger, Walter; Stanek, Johann; Wadsak, Wolfgang; Hacker, Marcus; Zeitlinger, Markus; Langer, Oliver (2017-05-04). "Effect of P-glycoprotein inhibition at the blood–brain barrier on brain distribution of (R)-[11C]verapamil in elderly vs. young subjects". British Journal of Clinical Pharmacology. 83 (9): 1991–1999. doi:10.1111/bcp.13301. ISSN   0306-5251. PMC   5555869 . PMID   28401570.
  3. 1 2 3 4 Kroemer, HeyoK.; Gautier, Jean-Charles; Beaune, Philipe; Henderson, Colin; Roland Wolf, C.; Eichelbaum, Michel (September 1993). "Identification of P450 enzymes involved in metabolism of verapamil in humans" . Naunyn-Schmiedeberg's Archives of Pharmacology. 348 (3): 332–337. doi:10.1007/bf00169164. ISSN   0028-1298. PMID   8232610.
  4. 1 2 Wang, Jian; Xia, Sumei; Xue, Weifang; Wang, Dawei; Sai, Yang; Liu, Li; Liu, Xiaodong (November 2013). "A semi-physiologically-based pharmacokinetic model characterizing mechanism-based auto-inhibition to predict stereoselective pharmacokinetics of verapamil and its metabolite norverapamil in human" . European Journal of Pharmaceutical Sciences. 50 (3–4): 290–302. doi:10.1016/j.ejps.2013.07.012. ISSN   0928-0987. PMID   23916407.
  5. ↑ Thompson, David C.; Bentzien, Jörg (December 2020). "Crowdsourcing and open innovation in drug discovery: recent contributions and future directions". Drug Discovery Today. 25 (12): 2284–2293. doi:10.1016/j.drudis.2020.09.020. ISSN   1359-6446. PMC   7529695 . PMID   33011343.
  6. ↑ Dadashzadeh, S.; Javadian, B.; Sadeghian, S. (2006). "The effect of gender on the pharmacokinetics of verapamil and norverapamil in human" . Biopharmaceutics & Drug Disposition. 27 (7): 329–334. doi:10.1002/bdd.512. ISSN   1099-081X.
  7. ↑ Gupta, Sk; Atkinson, L; Tu, T; Longstreth, Ja (1995). "Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil". British Journal of Clinical Pharmacology. 40 (4): 325–331. doi:10.1111/j.1365-2125.1995.tb04554.x. ISSN   1365-2125. PMC   1365151 . PMID   8554934.
  8. ↑ Gupta, Suneel K.; Yih, Betty M.; Atkinson, Linda; Longstreth, James (1995). "The Effect of Food, Time of Dosing, and Body Position on the Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil" . The Journal of Clinical Pharmacology. 35 (11): 1083–1093. doi:10.1002/j.1552-4604.1995.tb04031.x. ISSN   1552-4604.
  9. ↑ Choi, Dong-Hyun; Shin, Wan-Gyun; Choi, Jun-Shik (2008-05-01). "Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil" . European Journal of Clinical Pharmacology. 64 (5): 445–449. doi:10.1007/s00228-007-0447-5. ISSN   1432-1041.


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