Chemical: Drug
drospirenone

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Annotated Labels

  1. FDA Label for drospirenone,ethinyl estradiol and CYP2C19
  2. HCSC Label for drospirenone,ethinyl estradiol and F5,PROC,PROS1,SERPINC1

last updated 07/14/2014

1. FDA Label for drospirenone,ethinyl estradiol and CYP2C19

Informative PGx

Summary

The FDA-approved drug label for drospirenone and ethinyl estradiol (Yaz) notes that in vitro studies showed an inhibitory effect of drospirenone on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4. However, in vivo studies using omeprazole as a marker substrate showed that drospirenone has little propensity to interact to a significant extent with cytochrome P450 enzymes at a clinical dose level.

Annotation

Drospirenone and ethinyl estradiol (Yaz) is a combined oral contraceptive drug. The FDA-approved drug label notes that in vitro studies showed that drospirenone had an inibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4, but no influence on model substrates of CYP1A2 and CYP2D6. However, in vivo studies using omeprazole as a marker substrate showed no influence of drospirenone on clearance of omeprazole. This suggests that drospirenone has little propensity to interact with cytochrome P450 enzymes.

Excerpt from the drospirenone and ethinyl estradiol (Yaz) drug label:

In in vitro studies DRSP [drospirenone] did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19 and CYP3A4 with CYP2C19 being the most sensitive enzyme.

The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose). Based on the available results of in vivo and in vitro studies it can be concluded that, at clinical dose level, DRSP shows little propensity to interact to a significant extent with cytochrome P450 enzymes.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the drospirenone and ethinyl estradiol 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

  • CYP1A1
    • Precautions section
    • source: U.S. Food and Drug Administration
  • CYP1A2
    • Precautions section
    • source: U.S. Food and Drug Administration
  • CYP2C19
    • Precautions section
    • source: U.S. Food and Drug Administration
  • CYP2C9
    • Precautions section
    • source: U.S. Food and Drug Administration
  • CYP2D6
    • Precautions section
    • source: U.S. Food and Drug Administration
  • CYP3A4
    • metabolism/PK, Drug interactions section, Clinical pharmacology section, Precautions section
    • source: U.S. Food and Drug Administration

last updated 06/08/2015

2. HCSC Label for drospirenone,ethinyl estradiol and F5,PROC,PROS1,SERPINC1

Actionable PGx

Summary

The product monograph for drospirenone and ethinyl estradiol (YAZ) states that the drug is contraindicated in women with Factor V Leiden mutation, antithrombin-III-deficiency, protein C deficiency and protein S deficiency (among other contraindications), due to the risk for arterial or venous thrombosis.

Annotation

YAZ is indicated for conception control and treatment of moderate acne vulgaris. It is contraindicated in women who have a hereditary or acquired predisposition for venous or arterial thrombosis. One such predisposition is Factor V Leiden mutation - rs6025 within the F5 gene. Others are antithrombin III, protein C or protein S deficiency. These three proteins are encoded by the SERPINC1, PROC and PROS1 genes, respectively. Each of these predispositions and oral contraceptives themselves are known to independently increase the risk for thrombosis; together they may have a cumulative effect on thrombosis risk.

YAZ should not be used in women with: presence of severe or multiple risk factor(s) for arterial or venous thrombosis: hereditary or acquired predisposition for venous or arterial thrombosis, such as Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant).

For the complete product monograph text with sections containing pharmacogenetic information highlighted, see the drospirenone and ethinyl estradiol product monograph.

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


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

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.

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Overview

Generic Names
  • 6beta,7beta,15beta,16beta-dimethylene-3-oxo-17alpha-pregn-4-ene-21,17 carbolactone
  • DRSP
  • Drospirenona [inn-spanish]
  • Drospirenonum [inn-latin]
Trade Names
Brand Mixture Names
  • Yasmin (drospirenone + ethinylestradiol)
  • Yaz (drospirenone + ethinylestradiol)

PharmGKB Accession Id

PA164749409

Type(s):

Drug

Description

Drospirenone is a synthetic progestin that is an analog to spironolactone. It is found in a number of birth control formulations. Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has anti-mineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and is not androgenic.

Source: Drug Bank

Indication

For the prevention of pregnancy in women who elect an oral contraceptive.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Progestins such as drospirenone diffuse freely into target cells in the female reproductive tract, mammary gland, hypothalamus, and the pituitary and bind to the progesterone receptor. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge.

Source: Drug Bank

Pharmacology

Drospirenone differs from other synthetic progestins in that its pharmacological profile in preclinical studies shows it to be closer to the natural progesterone. As such it has anti-mineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and is not androgenic.

Source: Drug Bank

Food Interaction

Food reduces the rate of absorption, but not the extent of absorption.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Extensively metabolized following oral or intravenous administration. The two major metabolites are inactive and are formed independent of the CYP450 enzyme system. The metabolites are the acid form of drospirenone formed by opening of the lactone ring and the 4,5-dihydro-drospirenone-3-sulfate.

Source: Drug Bank

Protein Binding

97%

Source: Drug Bank

Absorption

Oral bioavailability is approximately 76%.

Source: Drug Bank

Half-Life

30 hours

Source: Drug Bank

Chemical Properties

Chemical Formula

C24H30O3

Source: Drug Bank

Isomeric SMILES

C[C@]12CCC(=O)C=C1[C@@H]3C[C@@H]3[C@@H]4[C@@H]2CC[C@]5([C@H]4[C@@H]6C[C@@H]6[C@@]57CCC(=O)O7)C

Source: Drug Bank

[H][C@@]12C[C@]1([H])[C@@]1([H])[C@]3([H])[C@]4([H])C[C@]4([H])[C@@]4(CCC(=O)O4)[C@@]3(C)CC[C@]1([H])[C@@]1(C)CCC(=O)C=C21

Source: Drug Bank

Canonical SMILES

C[C@]12CC[C@H]

Source: Drug Bank

Average Molecular Weight

366.4932

Source: Drug Bank

Monoisotopic Molecular Weight

366.219494826

Source: Drug Bank

SMILES

[H][C@@]12C[C@]1([H])[C@@]1([H])[C@]3([H])[C@]4([H])C[C@]4([H])[C@@]4(CCC(=O)O4)[C@@]3(C)CC[C@]1([H])[C@@]1(C)CCC(=O)C=C21

Source: Drug Bank

InChI String

InChI=1S/C24H30O3/c1-22-6-3-12(25)9-17(22)13-10-14(13)20-16(22)4-7-23(2)21(20)15-11-18(15)24(23)8-5-19(26)27-24/h9,13-16,18,20-21H,3-8,10-11H2,1-2H3/t13-,14+,15-,16+,18+,20-,21+,22-,23+,24+/m1/s1

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
AR (source: Drug Bank)
ESR1 (source: Drug Bank)
NR3C2 (source: Drug Bank)
PGR (source: Drug Bank)

Curated Information ?

EvidenceDrug
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
ketoconazole

Drug Interactions

Interaction Description
benazepril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
candesartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
candesartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
captopril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
cilazapril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
enalapril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
eprosartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
eprosartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
fosinopril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
heparin - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
irbesartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
irbesartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
lisinopril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
losartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
losartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
olmesartan - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
perindopril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
quinapril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
ramipril - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
telmisartan - drospirenone Telmisartan may increase the hyperkalemic effect of Drospirenone. Monitor for increased serum potassium concentrations during concomitant therapy. (source: Drug Bank)
telmisartan - drospirenone Telmisartan may increase the hyperkalemic effect of Drospirenone. Monitor for increased serum potassium concentrations during concomitant therapy. (source: Drug Bank)
thiopental - drospirenone Thiopental may decrease the effect of Drospirenone. Contraceptive failure may occur. Alternative nonhomomonal contraception should be used during concomitant therapy. (source: Drug Bank)
thiopental - drospirenone Thiopental may decrease the effect of Drospirenone. Contraceptive failure may occur. Alternative nonhomomonal contraception should be used during concomitant therapy. (source: Drug Bank)
trandolapril - drospirenone Increased risk of hyperkalemia. Monitor serum potassium levels. (source: Drug Bank)
treprostinil - drospirenone Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use. (source: Drug Bank)
triamterene - drospirenone Increased risk of hyperkaliemia (source: Drug Bank)
warfarin - drospirenone Drospirenone may alter the anticoagulant effect of warfarin. Concomitant therapy should be avoided. Monitor for changes in coagulation status if drospirenone is initiated, discontinued or dose changed. (source: Drug Bank)

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Prevent
Contraindicated With

Publications related to drospirenone: 1

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and the hormone drospirenone in combination with ethinylestradiol or estradiol. British journal of clinical pharmacology. 2015. Wiesinger Herbert, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB01395
ChEBI:
50838
KEGG Drug:
D03917
PubChem Compound:
68873
PubChem Substance:
12014580
46507653
Drugs Product Database (DPD):
2261731
ChemSpider:
62105
Therapeutic Targets Database:
DAP001206

Clinical Trials

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

No trials found.

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Sources for PharmGKB drug information: DrugBank, PubChem.