Norverapamil

Norverapamil
Names
	IUPAC name (RS)-2-(3,4-Dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethylamino]-2-isopropylpentanenitrile
Identifiers
CAS Number	67018-85-3 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:132050 ;
ChemSpider	94724 ;
ECHA InfoCard	100.060.476
EC Number	266-544-8;
PubChem CID	104972;
UNII	957Z3K3R56 ;
CompTox Dashboard (EPA)	DTXSID80873799 ;
	InChI 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 Key: UPKQNCPKPOLASS-UHFFFAOYSA-N ; 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;
	SMILES CC(C)C(CCCNCCC1=CC(=C(C=C1)OC)OC)(C#N)C2=CC(=C(C=C2)OC)OC;
Properties
Chemical formula	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). verify (what is ?) Infobox references

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]

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]

References

^ 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)
^ ^a ^b ^c ^d ^e 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.
^ ^a ^b ^c ^d 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.
^ ^a ^b 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.
^ 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.

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[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)

[:0-2] 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.

[:1-3] 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.

[:2-4] 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.

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