Solifenacin

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Solifenacin
Solifenacin Structural Formulae V.1.svg
Systematic (IUPAC) name
1-azabicyclo[2.2.2]oct-3-yl (1R)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate
Clinical data
Trade names Vesicare
AHFS/Drugs.com Monograph
MedlinePlus a605019
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 90%
Protein binding 98%
Metabolism CYP3A4
Metabolites Glucuronide, N-oxide, others
Biological half-life 45 to 68 hours
Excretion Renal (69.2%) and fecal (22.5%)
Identifiers
CAS Number 242478-37-1 N
ATC code G04BD08 (WHO)
PubChem CID 154059
IUPHAR/BPS 7483
DrugBank DB01591 YesY
ChemSpider 135771 N
UNII A8910SQJ1U YesY
KEGG DG00481 N
ChEMBL CHEMBL1734 N
Synonyms YM905
Chemical data
Formula C23H26N2O2
Molar mass 362.465 g/mol
 NYesY (what is this?)  (verify)

Solifenacin (INN, trade name Vesicare) is a medicine of the antimuscarinic class and was developed for treating contraction of overactive bladder[1] with associated problems such as increased urination frequency and urge incontinence.[2] It is manufactured and marketed by Astellas, GlaxoSmithKline[3] and Teva Pharmaceutical Industries.[citation needed]

Contraindications[edit]

Solifenacin is contraindicated for people with urinary retention, gastric retention, uncontrolled or poorly controlled closed-angle glaucoma, severe liver disease (Child-Pugh class C),[4] and hemodialysis.[2]

Long QT syndrome is not a contraindication although solifenacin, like tolterodine and darifenacin, binds to hERG channels of the heart and may prolong the QT interval. This mechanism appears to be seldom clinically relevant.[5]

Side effects[edit]

Main article: Anticholinergic

The most common side effects of solifenacin are dry mouth, blurred vision, and constipation. As all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration.[4]

Interactions[edit]

Solifenacin is metabolized in the liver by the cytochrome P450 enzyme CYP3A4. When administered concomitantly with drugs that inhibit CYP3A4, such as ketoconazole, the metabolism of solifenacin is impaired, leading to an increase in its concentration in the body and a reduction in its excretion.[4]

As stated above, solifenacin may also prolong the QT interval. Therefore, administering it concomitantly with drugs which also have this effect, such as moxifloxacin or pimozide, can theoretically increase the risk of arrhythmia.[3]

Pharmacology[edit]

Mechanism of action[edit]

Solifenacin is a competitive cholinergic receptor antagonist, selective for the M3 receptor subtype. The binding of acetylcholine to these receptors, particularly M3, plays a critical role in the contraction of smooth muscle. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half life, a once-a-day dose can offer 24-hour control of the urinary bladder smooth muscle tone.[2]

Pharmacokinetics[edit]

Peak plasma concentrations are reached 3 to 8 hours after absorption from the gut. In the bloodstream, 98% of the substance are bound to plasma proteins, mainly acidic ones. Metabolism is mediated by the liver enzyme CYP3A4 and possibly others. There is one known active metabolite, 4R-hydroxysolifenacin, and three inactive ones, the N-glucuronide, the N-oxide and the 4R-hydroxy-N-oxide. The elimination half-life is 45 to 68 hours. 69% of the substance, both in its original form and as metabolites, are excreted renally and 23% via the feces.[2]

Chemistry[edit]

Atropine for comparison

Like other anticholinergics, solifenacin is an ester of a carboxylic acid containing (at least) an aromatic ring with an alcohol containing a nitrogen atom. While in the prototype anticholinergic atropine the alcohol is tropine, solifenacin has another bicycle, quinuclidinyl alcohol.

The substance is a basic yellow oil, while the form used in tablets, solifenacin succinate, consists of white to slightly yellowish crystals.[6]

History[edit]

The compound was studied using animal models by the Yamanouchi Pharmaceutical Co., Ltd. of Tokyo, Japan. It was known as YM905 when under study in the early 2000s.[7]

Society and culture[edit]

Economics[edit]

A 2006 cost-effectiveness study found that 5 mg solifenacin had the lowest cost and highest effectiveness among anticholinergic drugs used to treat overactive bladder in the United States, with an average medical cost per successfully treated patient of $6863 per year.[8]

References[edit]

  1. ^ Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 343. ISBN 1437727883. 
  2. ^ a b c d Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8659–62. ISBN 978-3-85200-181-4. 
  3. ^ a b Drugs.com: Monograph on Vesicare.
  4. ^ a b c Lexi-Comp (December 2009). "Solifenacin". The Merck Manual Professional. Retrieved 10 June 2011. 
  5. ^ "Vesicare 5mg & 10mg film-coated tablets". eMC. Retrieved 13 December 2015. 
  6. ^ The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals (14 ed.). 2006. p. 1494. ISBN 978-0-911910-00-1. 
  7. ^ Kobayashi, S.; et al. (July 2001). "Effects of YM905, a Novel Muscarinic M3-Receptor Antagonist, on Experimental Models of Bowel Dysfunction In Vivo". Jpn. J. Pharmacol. 86 (3): 281–288. PMID 11488427. 
  8. ^ Ko Y, Malone DC, Armstrong EP (Dec 2006). "Pharmacoeconomic evaluation of antimuscarinic agents for the treatment of overactive bladder". Pharmacotherapy. 26 (12): 1694–702. doi:10.1592/phco.26.12.1694. PMID 17125433.