DOXAZOSIN

Details

Stereochemistry	RACEMIC
Molecular Formula	C23H25N5O5
Molecular Weight	451.4751
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

COC1=CC2=NC(=NC(N)=C2C=C1OC)N3CCN(CC3)C(=O)C4COC5=CC=CC=C5O4

InChI

InChIKey=RUZYUOTYCVRMRZ-UHFFFAOYSA-N

InChI=1S/C23H25N5O5/c1-30-18-11-14-15(12-19(18)31-2)25-23(26-21(14)24)28-9-7-27(8-10-28)22(29)20-13-32-16-5-3-4-6-17(16)33-20/h3-6,11-12,20H,7-10,13H2,1-2H3,(H2,24,25,26)

HIDE SMILES / InChI

Molecular Formula	C23H25N5O5
Molecular Weight	451.4751
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description

Doxazosin mesylate is a quinazoline compound sold by Pfizer under the brand name CARDURA. CARDURA is indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). CARDURA may be used in all BPH patients whether hypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with CARDURA monotherapy. CARDURA provides rapid improvement in symptoms and urinary flow rate in 66–71% of patients. CARDURA is also indicated for the treatment of hypertension. CARDURA may be used alone or in combination with diuretics, beta-adrenergic blocking agents, calcium channel blockers, or angiotensin-converting enzyme inhibitors. Doxazosin acts by inhibiting the postsynaptic alpha(1)-adrenoceptors on vascular smooth muscle. This inhibits the vasoconstrictor effect of circulating and locally released catecholamines (epinephrine and norepinephrine), resulting in peripheral vasodilation.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Alpha-1a adrenergic receptor	Antagonist	9.27 null [pKi]
Alpha-1b adrenergic receptor	Antagonist	9.09 null [pKi]
Alpha-1d adrenergic receptor	Antagonist	9.09 null [pKi]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Benign prostatic hyperplasia	Primary		Approved	CARDURA
Hypertension	Primary		Approved	CARDURA

C_max

Value	Dose	Analyte	Population
9.7 ng/mL	1 mg single, oral	DOXAZOSIN plasma	Homo sapiens
13.6 ng/mL	1 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
14.3 ng/mL	1 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
42.3 ng/mL	4 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
65.5 ng/mL	8 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
151.7 ng/mL	16 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
162 ng × h/mL	1 mg single, oral		DOXAZOSIN plasma	Homo sapiens
268 ng × h/mL	1 mg 1 times / day steady-state, oral		DOXAZOSIN plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
12.9 h	1 mg single, oral	DOXAZOSIN plasma	Homo sapiens
15 h	1 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
11.9 h	1 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
12.8 h	4 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
8.3 h	8 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens
11.6 h	16 mg 1 times / day steady-state, oral	DOXAZOSIN plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
60 mg single, oral Overdose	healthy, 19 years	Disc. AE: Sinus tachycardia...
16 mg single, oral Highest studied dose	unhealthy, adult	DLT: Postural edema...
4 mg 1 times / day steady, oral Recommended	healthy, adult	Disc. AE: Orthostatic dizziness...
16 mg 1 times / day steady, oral Highest studied dose	unhealthy, mean 59 years	Disc. AE: Fatigue, Urinary incontinence... Other AEs: Rhinitis...
8 mg 1 times / day steady, oral	unhealthy	Other AEs: Nausea, Constipation...

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AEs

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AE	Significance	Dose	Population
Sinus tachycardia	1 patient Disc. AE	60 mg single, oral Overdose	healthy, 19 years
Postural edema	2.7% DLT	16 mg single, oral Highest studied dose	unhealthy, adult
Orthostatic dizziness	1 patient Disc. AE	4 mg 1 times / day steady, oral Recommended	healthy, adult
Rhinitis	1 patient	16 mg 1 times / day steady, oral Highest studied dose	unhealthy, mean 59 years
Urinary incontinence	2 patients Disc. AE	16 mg 1 times / day steady, oral Highest studied dose	unhealthy, mean 59 years

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate	substrate	substrate	inhibitor

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP2B1 P-gp BCRP NTCP OATP1B1 OATP1B3 OCT1	CYP2C19

Drug as perpetrator

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Target	Modality	Activity
OATP1B1	inhibitor	no
OATP1B3	inhibitor	no
OATP2B1	inhibitor	no
BCRP	inhibitor	yes
NTCP	inhibitor	yes

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4	substrate	major	likely (co-administration study)
CYP2C19	substrate	minor
CYP2C9	substrate	minor
CYP2D6	substrate	minor

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG	inhibitor

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4708	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4708
eMolecules	537813	https://www.emolecules.com/cgi-bin/more?vid=537813
MolPort	MolPort-001-684-491	https://www.molport.com/shop/molecule-link/MolPort-001-684-491

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PubMed

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Title	Date	PubMed
Quality-of-life assessment in patients with benign prostatic hyperplasia: effects of various interventions.	2001	11735675
Efficacy and tolerability of drugs for treatment of benign prostatic hyperplasia.	2001	11583366
Effects of two atypical neuroleptics, olanzapine and risperidone, on the function of the urinary bladder and the external urethral sphincter in anesthetized rats.	2001	11580866
Renal hemodynamic effects of captopril and doxazosin during slight physical activity in hypertensive patients with type-1 diabetes mellitus.	2001	11174009
Baseline characteristics of the diabetic participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).	2001 Apr	11315826

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Patents

Sample Use Guides

In Vivo Use Guide

Usual Adult Dose for Hypertension Initial dose: 1 mg orally once a day. Maintenance dose: 1 to 16 mg orally once a day. Usual Adult Dose for Benign Prostatic Hyperplasia Initial dose: Immediate-release: 1 mg orally once a day. Extended-release: 4 mg orally once a day with breakfast Maintenance dose: Immediate-release: 1 to 8 mg orally once a day. Extended-release: 4 to 8 mg orally once a day with breakfast. Depending on the patient's symptomatic response and tolerability, the dose may be increased to 8 mg (the maximum recommended dose). The recommended titration interval is 3 to 4 weeks.

Route of Administration: Oral

In Vitro Use Guide

Ring segments of splanchnic, peripheral, coronary, pulmonary and uterine conduit arteries obtained during surgery were studied in tissue baths. Resistance arteries dissected from various sites were studied in a myograph. Both conduit and resistance vessels contracted in response to the alpha 1-agonist phenylephrine (10(-7) to 10(-4) mol/l), an effect that was antagonized by the alpha 1-antagonist doxazosin (10(-8) to 10(-6) mol/l).