Doxofylline

266.25

266.25

274-239-6

MPM23GMO7Z

759645

DTXSID7022968

R - Respiratory system

29399990

76.9

-0.70

1.6±0.1 g/cm3

144-145.5 °C

505.2±53.0 °C at 760 mmHg

259.3±30.9 °C

1.700

H2O: soluble

LD50 in mice (mg/kg): 841 orally; 215.6 i.v.; in rats: 1022.4 orally, 445 i.p. (Franzone)

NONH for all modes of transport

36/37/38

26-36/37

XH5135000

Xi

P301 + P312 + P330

H302

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P280, P301+P312, P302+P352, P305+P351+P338, P321, P330, P332+P313, P337+P313, P362, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Oral LD50 in rat and mouse are 965 mg/kg and 841 mg/kg, respectively. Intraperitoneal LD50 in rat and mouse are 426 mg/kg and 396 mg/kg, respectively [MSDS].

At pH 7.4, the fraction of plasma protein binding is about 48%.

Indicated for the treatment of chronic obstructive pulmonary disease (COPD), bronchial asthma and pulmonary disease with spastic bronchial component.

Doxofylline is a methylxanthine bronchodilator with potent bronchodilator activity comparable to that of theophylline. In animal studies, doxofylline demonstrated to attenuate bronchoconstriction, inflammatory actions and the release of thromboxane A2 (TXA2) when challenged with platelet-activating factor. Doxofylline does not demonstrate direct inhibition of any histone deacetylase (HDAC) enzymes or known PDE enzyme isoforms and did not act as an antagonist at A2 or A2 receptors. The affinity for adenosine A1, A2A and A2B receptors are reported to be all higher than 100 µM. It only displays an inhibitory action against PDE2A1 and antagonism at adenosine A(2A) at high concentrations. A study demonstrated that doxofylline interacts with β2-adrenoceptors to induce blood vessel relaxation and airway smooth muscle relaxation. In dog studies, doxofylline decreased airway responsiveness at a dose that did not affect heart rate and respiratory rate.

Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)|Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. (See all compounds classified as Phosphodiesterase Inhibitors.)|Agents that suppress cough. They act centrally on the medullary cough center. EXPECTORANTS, also used in the treatment of cough, act locally. (See all compounds classified as Antitussive Agents.)

After repeated administrations doxofylline reaches the steady-state in about 4 days. Following oral administration of 400 mg doxofylline twice daily for 5 days in adults with chronic bronchitis, the peak plasma concentrations (Cmax) at steady state ranged from 5.78 to 20.76 mcg/mL. The time to reach maximum concentration (Tmax) was 1.19 ± 0.19 hours. The absolute bioavailability of doxofylline in healthy subjects was 63 ± 25%.|Less than 4% of an orally administered dose is excreted unchanged in the urine due to extensive hepatic metabolism.|Doxofylline demonstrates a short distribution phase following intravenous administration of 100 mg given in adults with chronic bronchitis. As methylxanthines are distributed to all body compartments, doxofylline may be detected in breast milk and placenta.|Following oral administration of 400 mg doxofylline twice daily for 5 days, the total clearance was 555.2 ± 180.6 mL/min.

Doxofylline is thought to undergo hepatic metabolism which accounts for 90% of total drug clearance. β-hydroxymethyltheophylline was detected in the serum and urine after oral administration of 400 mg given in healthy subjects. The circulating metabolite was devoid of any significant pharmacological activity.

Following administration of a single intravenous dose of 100 mg over 10 minutes in adults with chronic bronchitis, the elimination half life of doxofylline was 1.83 ± 0.37 hours. Following oral administration of 400 mg twice daily for 5 days in adults with chronic bronchitis, the mean elimination half life was 7.01 ± 0.80 hours.

The main mechanism of action of doxofylline is unclear. One of the mechanisms of action of is thought to arise from the inhibition of phosphodiesterase activity thus increasing the levels of cAMP and promoting smooth muscle relaxation. The interaction of doxofylline with beta-2 adrenoceptors was demonstrated by a study using nonlinear chromatography, frontal analysis and molecular docking. Serine 169 and serine 173 residues in the receptor are thought to be critical binding sites for doxofylline where hydrogen bonds are formed. Via mediating the actions of beta-2 adrenoceptors, doxofylline induces blood vessel relaxation and airway smooth muscle relaxation. There is also evidence that doxofylline may exert anti-inflammatory actions by reducing the pleurisy induced by the inflammatory mediator platelet activating factor (PAF) according to a rat study. It is suggested that doxofylline may play an important role in attenuating leukocyte diapedesis, supported by mouse preclinical studies where doxofylline administration was associated with inhibited leukocyte migration across vascular endothelial cells in vivo and in vitro.Unlike theophylline, doxofylline does not inhibit tumor necrosis factor-induced interleukin (IL)-8 secretion in ASM cells.

2-(7'-theophyllinemethyl)1,3-dioxolane