Absorption, Distribution and Excretion
AFTER IV DOXAPRAM-HCL BOLUS INJECTIONS OR BRIEF INFUSIONS IN HEALTHY VOLUNTEER, PLASMA CONCN DECLINED IN MULTI-EXPONENTIAL FASHION. VOL OF DISTRIBUTION WAS 1.51 KG-1, & WHOLE BODY CLEARANCE WAS 370 ML MIN-1.
ENTERIC-COATED CAPSULES OF DOXAPRAM WERE ABSORBED RAPIDLY AFTER INITIAL DELAY, & SYSTEMIC AVAILABILITY WAS APPROX 60%. LESS THAN 5% OF AN IV DOSE WAS EXCRETED UNCHANGED IN URINE IN 24 HR.

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Metabolism / Metabolites
DOXAPRAM YIELDS 4-(2-MORPHOLINOETHYL)-3,3-DIPHENYLPYRROLIDIN-2-ONE, & 1-ETHYL-4-(2-(3-OXOMORPHOLINO)ETHYL)-3,3-DIPHENYLPYRROLIDIN-2-ONE IN DOGS. PITTS, JE, BRUCE, RB, & FOREHAND, JB, XENOBIOTICA, 3, 73 (1973). /FROM TABLE/
AFTER IV DOXAPRAM-HCL BOLUS INJECTIONS OR BRIEF INFUSIONS IN HEALTHY VOLUNTEERS, A METABOLITE AHR 5955 WAS PRESENT IN PLASMA IN AMT COMPARABLE TO PARENT COMPD & HAD A SIMILAR HALF-LIFE.

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Biological Half-Life
AFTER IV DOXAPRAM-HCL BOLUS INJECTIONS OR BRIEF INFUSIONS IN HEALTHY VOLUNTEER, PLASMA CONCN DECLINED IN MULTI-EXPONENTIAL FASHION. HALF-LIFE FROM 4-12 HR WAS 3.4.

[1]. The ventilatory stimulant doxapram inhibits TASK tandem pore (K2P) potassium channel function but does not affect minimum alveolar anesthetic concentration. Anesth Analg, 2006, 102(3), 779-785.

[2]. Peers, C., Effects of doxapram on ionic currents recorded in isolated type I cells of the neonatal rat carotid body. Brain Res, 1991. 568(1-2): p. 116-22.

[3]. Doxapram stimulates dopamine release from the intact rat carotid body in vitro. Neurosci Lett, 1995. 187(1): p. 25-8.

Doxapram is a member of the class of pyrrolidin-2-ones that is N-ethylpyrrolidin-2-one in which both of the hydrogens at the 3 position (adjacent to the carbonyl group) are substituted by phenyl groups, and one of the hydrogens at the 4 position is substituted by a 2-(morpholin-4-yl)ethyl group. A central and respiratory stimulant with a brief duration of action, it is used (generally as the hydrochloride or the hydrochloride hydrate) as a temporary treatment of acute respiratory failure, particularly when superimposed on chronic obstructive pulmonary disease, and of postoperative respiratory depression. It has also been used for treatment of postoperative shivering. It has a role as a central nervous system stimulant. It is a member of morpholines and a member of pyrrolidin-2-ones.
A central respiratory stimulant with a brief duration of action. (From Martindale, The Extra Pharmocopoeia, 30th ed, p1225)
Doxapram is a Respiratory Stimulant. The physiologic effect of doxapram is by means of Increased Medullary Respiratory Drive.
Doxapram is a respiratory stimulant with analeptic activity. Doxapram, independent of oxygen levels, directly stimulates the peripheral carotid chemoreceptors, possibly by inhibiting the potassium channels of type I cells within the carotid body, thereby stimulating catecholamines release. This results in the prevention or reversal of both narcotic- and CNS depressant-induced respiratory depression.
A central respiratory stimulant with a brief duration of action. (From Martindale, The Extra Pharmocopoeia, 30th ed, p1225)
See also: Doxapram Hydrochloride (has salt form).

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Drug Indication
For use as a temporary measure in hospitalized patients with acute respiratory insufficiency superimposed on chronic obstructive pulmonary disease.
FDA Label

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Mechanism of Action
Doxapram produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. It is thought to stimulate the carotid body by inhibiting certain potassium channels.
DOXAPRAM...STIMULATE ALL LEVELS OF CEREBROSPINAL AXIS. ADEQUATE DOSES PRODUCE TONIC-CLONIC CONVULSIONS SIMILAR IN PATTERN TO THOSE PRODUCED BY PENTYLENETETRAZOL. ...ACT BY ENHANCING EXCITATION RATHER THAN BY BLOCKING CENTRAL INHIBITION.

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Therapeutic Uses
Central Nervous System Stimulants; Respiratory System Agents
MEDICATION (VET): TO INCR VENTILATION & DECR SLEEPING TIME IN CATS & DOGS UNDER PENTOBARBITAL ANESTHESIA, & OCCASIONALLY IN ANESTHETIZED HORSES.
RESP CAN BE STIMULATED BY...DOSES THAT PRODUCE LITTLE GENERALIZED EXCITATION. DIRECT MEDULLARY STIMULATION IS LARGELY RESPONSIBLE FOR THIS EFFECT, BUT INDIRECT STIMULATION BY ACTIVATION OF PERIPHERAL CHEMORECEPTORS MAY... CONTRIBUTE. DURATION OF STIMULATION IS TRANSIENT AFTER SINGLE IV DOSE & SELDOM LASTS FOR...5-10 MIN.
DOXAPRAM...USED AS TEMPORARY MEASURES TO CORRECT ACUTE RESP INSUFFICIENCY IN PT WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. INTERMITTENT OR CONTINUOUS INFUSION IS NECESSARY FOR SUSTAINED RESP STIMULATION & REDUCTION IN CARBON DIOXIDE TENSION...
For more Therapeutic Uses (Complete) data for DOXAPRAM (7 total), please visit the HSDB record page.

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Drug Warnings
BECAUSE OF EFFECTIVENESS OF CONTROLLED VENTILATION & STANDARD SUPPORTIVE THERAPY IN TREATMENT OF VENTILATORY FAILURE, DOXAPRAM NORMALLY SHOULD NOT BE USED TO STIMULATE VENTILATION IN PT WITH DRUG-INDUCED COMA OR AN EXACERBATION OF CHRONIC LUNG DISEASES. /HYDROCHLORIDE/
DOXAPRAM IS CONTRAINDICATED IN PT WITH CONVULSIVE DISORDERS, HYPERTENSION, CEREBRAL EDEMA, HYPERTHYROIDISM, OR PHEOCHROMOCYTOMA & IN THOSE TAKING MONOAMINE OXIDASE INHIBITORS OR ADRENERGIC AGENTS. /HYDROCHLORIDE/

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Pharmacodynamics
Doxapram is an analeptic agent (a stimulant of the central nervous system). The respiratory stimulant action is manifested by an increase in tidal volume associated with a slight increase in respiratory rate. A pressor response may result following doxapram administration. Provided there is no impairment of cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following doxapram administration, an increased release of catecholamines has been noted.

C24H30N2O2

378.51

378.23

C, 76.16; H, 7.99; N, 7.40; O, 8.45

309-29-5

Doxapram hydrochloride hydrate;7081-53-0

3156

White to off-white crystalline powder.

1.1±0.1 g/cm3

536.4±50.0 °C at 760 mmHg

217-219
MP: 123-124 °C /BENZOATE/

278.2±30.1 °C

0.0±1.4 mmHg at 25°C

1.562

3.23

0

3

6

28

487

0

O=C1N(CC)CC(CCN2CCOCC2)C1(C3=CC=CC=C3)C4=CC=CC=C4

XFDJYSQDBULQSI-UHFFFAOYSA-N

InChI=1S/C24H30N2O2/c1-2-26-19-22(13-14-25-15-17-28-18-16-25)24(23(26)27,20-9-5-3-6-10-20)21-11-7-4-8-12-21/h3-12,22H,2,13-19H2,1H3

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)