Chemical: Drug
tiotropium

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last updated 10/25/2013

1. FDA Label for tiotropium and CYP2D6

Informative PGx

Summary

Tiotropium is an inhalation powder used daily for the treatment of bronchospasms associated with chronic obstructive pulmonary disease (COPD), and believed to be in small part metabolized by CYP2D6 and CYP3A4. This drug-biomarker pair was previously in the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" but has subsequently been removed.

Annotation

Tiotropium is an inhaled long-acting, antimuscarinic agent for the treatment of chronic obstructive pulmonary disease (COPD). It inhibits the M3-receptors of the airway smooth muscle leading to bronchodilation. Although mostly excreted unchanged, it may in some part be metabolized by CYP2D6 and CYP3A4. This drug-biomarker pair was previously in the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" but has subsequently been removed.

Excerpt from the Tiotropium (Spiriva) drug label:

In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations did not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Tiotropium (Spiriva) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Pulmonary Disease, Chronic Obstructive
    • Indications & usage section, Warnings section, Adverse reactions section
    • source: PHONT
  • CYP1A1
    • Pharmacokinetics section
    • source: U.S. Food and Drug Administration
  • CYP1A2
    • Pharmacokinetics section
    • source: U.S. Food and Drug Administration
  • CYP2B6
    • Pharmacokinetics section
    • source: U.S. Food and Drug Administration
  • CYP2D6
    • metabolism/PK, Clinical pharmacology section, Pharmacokinetics section
    • source: U.S. Food and Drug Administration
  • CYP2E1
    • Pharmacokinetics section
    • source: U.S. Food and Drug Administration
  • CYP3A4
    • metabolism/PK, Clinical pharmacology section, Pharmacokinetics section
    • source: U.S. Food and Drug Administration

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all variant annotations for tiotropium

Gene ? Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available CA VA
rs1042713 NC_000005.10:g.148826877G=, NC_000005.10:g.148826877G>A, NC_000005.9:g.148206440G=, NC_000005.9:g.148206440G>A, NG_016421.1:g.5285A=, NG_016421.1:g.5285A>G, NM_000024.5:c.46A=, NM_000024.5:c.46A>G, NP_000015.1:p.Arg16=, NP_000015.1:p.Arg16Gly, XM_005268382.1:c.46G=, XM_005268382.1:c.46G>A, XM_005268383.1:c.46G=, XM_005268383.1:c.46G>A, XP_005268439.1:p.Gly16=, XP_005268439.1:p.Gly16Arg, XP_005268440.1:p.Gly16=, XP_005268440.1:p.Gly16Arg, rs17287432, rs17334179, rs17334242, rs17721693, rs17839749, rs17846639, rs17859732, rs3182174, rs3729940, rs52812686, rs56964295
G > G
SNP
R16G
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Generic Names
  • Tiotropium bromide
Trade Names
  • Spiriva
Brand Mixture Names

PharmGKB Accession Id

PA164769056

Type(s):

Drug

Description

Tiotropium is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). Tiotropium is a muscarinic receptor antagonist, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.

Source: Drug Bank

Pharmacogenetics

Pharmacokinectics

Tiotropium is a bronchodilator used in the treatment of chronic obstructive pulmonary disease (COPD).

It is an anticholinergic, which relaxes airway smooth muscle by blocking cholinergic tone. From the lungs, there is rapid absorption into the circulation with peak plasma levels attained a maximum five minutes post dose with subsequent rapid decline in less than 1 hour to very low levels [Article:10069510]. Metabolism of absorbed drug is minimal and excretion is largely through the kidneys [Article:19292598]. Although in vitro studies suggest that cytochrome P450 oxidation, possibly involving CYP2D6 and CYP3A4 enzymes, may have a minor role [Article:15350163].

Pharmacodynamics

Plasma levels of tiotropium are unlikely to provide functionally relevant systemic occupancy of muscarinic receptors in agreement with a relatively low incidence of systemic antimuscarinic side effects in the clinical trials [Article:10069510]. In vitro studies showed that tiotropium dissociates very slowly from M1 receptors (CHRM1) and, in particular, M3 receptors (CHRM3) and more rapidly from M2 receptors (CHRM2) [Articles:10069510, 10673478]. The slow dissociation of tiotropium from CHRM3 results in a long duration of action [Article:10069510].

Source: PharmGKB

Indication

Used in the management of chronic obstructive pulmonary disease (COPD).

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Tiotropium is a muscarinic receptor antagonist, often referred to as an antimuscarinic or anticholinergic agent. Although it does not display selectivity for specific muscarinic receptors, on topical application it acts mainly on M3 muscarinic receptors located in the airways to produce smooth muscle relaxation, thus producing a bronchodilatory effect.

Source: Drug Bank

Pharmacology

Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies prevention of methacholine-induced bronchoconstriction effects were dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

The extent of biotransformation appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which bind to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. Via inhibition studies, it is evident that CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose.

Source: Drug Bank

Protein Binding

72% bound to plasma proteins.

Source: Drug Bank

Absorption

Bioavailability is 19.5% following administration by inhalation. Oral solutions of tiotropium have an absolute bioavailability of 2-3%.

Source: Drug Bank

Half-Life

5-6 days

Source: Drug Bank

Toxicity

No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7,300, 120,000, and 850 times the recommended human daily dose on a mg/m2 basis, respectively.

Source: Drug Bank

Clearance

Source: Drug Bank

Route of Elimination

Intravenously administered tiotropium was mainly excreted unchanged in urine (74%). After dry powder inhalation, urinary excretion was 14% of the dose, the remainder being mainly non-absorbed drug in the gut which was eliminated via the feces.

Source: Drug Bank

Volume of Distribution

  • 32 L/kg

Source: Drug Bank

Chemical Properties

Chemical Formula

C19H22NO4S2

Source: Drug Bank

Canonical SMILES

C[N+]1(C)[C@H]

Source: Drug Bank

Average Molecular Weight

392.512

Source: Drug Bank

Monoisotopic Molecular Weight

392.099024577

Source: Drug Bank

SMILES

C[N+]1(C)[C@H]2CC(C[C@@H]1[C@@H]1O[C@H]21)OC(=O)C(O)(C1=CC=CS1)C1=CC=CS1

Source: Drug Bank

InChI String

InChI=1S/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16+,17-

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
CHRM1 (source: Drug Bank)
CHRM2 (source: Drug Bank)
CHRM3 (source: Drug Bank)

Drug Interactions

Interaction Description
tacrine - tiotropium The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Tiotropium, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents. (source: Drug Bank)
trimethobenzamide - tiotropium Trimethobenzamide and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects. (source: Drug Bank)
triprolidine - tiotropium Triprolidine and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects. (source: Drug Bank)
triprolidine - tiotropium Triprolidine and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects. (source: Drug Bank)
trospium - tiotropium Trospium and Tiotropium, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects. (source: Drug Bank)

Curated Information ?

Publications related to tiotropium: 6

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Additive role of tiotropium in severe asthmatics and Arg16Gly in ADRB2 as a potential marker to predict response. Allergy. 2009. Park H-W, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD. Treatments in respiratory medicine. 2004. Keam Susan J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 2002. Casaburi R, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The pharmacological properties of tiotropium. Chest. 2000. Barnes P J. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life sciences. 1999. Disse B, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0597-0075-75
DrugBank:
DB01409
PubChem Compound:
5487426
PubChem Substance:
12014767
Drugs Product Database (DPD):
2246793
Therapeutic Targets Database:
DAP000344
FDA Drug Label at DailyMed:
820839ef-e53d-47e8-a3b9-d911ff92e6a9

Clinical Trials

These are trials that mention tiotropium and are related to either pharmacogenetics or pharmacogenomics.

No trials found.

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Sources for PharmGKB drug information: DrugBank, PubChem.