Identification of Doxapram Metabolites using High Pressure Ion Exchange Chromatography and Mass Spectroscopy

Pitts, Jefferson E.; Bruce, Robert; Forehand, J. B.

doi:10.3109/00498257309151502

Cited by 28 publications

(5 citation statements)

References 5 publications

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“…Our data show that doxapram is metabolized rapidly to ketodoxapram. Pitts et al 7 previously suggested that ketodoxapram is degraded to AHR 5904 by the opening of the morpholine ring in adult dogs. This is supported by the stable concentrations of ketodoxapram in the presence of increasing plasma concentrations of AHR 5904 during treatment.…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal Absorption of Doxapram in Neonates

Bairam¹,

Akramoff-Gershan²,

Beharry³

et al. 1991

Amer J Perinatol

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Doxapram was administered orally to six premature babies (3 males, 3 females) with refractory apnea at a mean gestational age of 29 +/- 2.3 weeks, mean birthweight of 1142 +/- 359 gm and a mean postnatal age of 24 days. They received 12, 24, and 36 mg/kg/6 hr on day 1, 2, and 3, respectively, assuming a bioavailability of 50%. Serial plasma doxapram concentrations, determined by high-performance liquid chromatography, increased with incremental doses. The drug underwent oxidative metabolism, producing ketodoxapram, the plasma concentration of which remained stable during treatment. The ratio of plasma concentrations to oral doses ranged from 0.10 to 0.12, suggesting that doxapram is poorly absorbed in the newborn. Oral doxapram may replace the intravenous infusion but doses may have to be increased to, but not exceeding, 24 mg/kg/6 hr to achieve therapeutic plasma concentrations. Interpatient variability, poor absorption and gastrointestinal adverse effects caution against the routine use of oral doxapram.

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Section: Discussionmentioning

confidence: 99%

Gastrointestinal Absorption of Doxapram in Neonates

Bairam¹,

Akramoff-Gershan²,

Beharry³

et al. 1991

Amer J Perinatol

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“…I1 and 111) and oxidation followed by conjugation (Metabolite IV) along known pathways that are relatively common in the horse. Metabolite I has been identified previously as a doxapram metabolite in dogs and man (Bruce er a1 1965;Nichol, Vine, Thomas and Moore 1980) and Metabolite I1 has been identified in dogs (Pitts et a/ 1973). Metabolites I11 and IV have not been reported previously, although Pitts et a/ (1973) expressed surprise that no aromatic-ring hydroxylated metabolites such as Metabolite IV were found in their investigation of doxapram metabolism in dogs.…”

Section: Discussionmentioning

confidence: 95%

“…The molecular ion at m/z 350 was confirmed by the pseudomolecular ion at m/z 351 in the methane CI mass spectrum. The electron-impact mass spectrum contained an ion at m/z 236 but none at m/z 264, indicating no change in the pyrrolidinone ring or the phenyl groups but loss of the N-ethyl moiety (Pitts, Bruce and Forehand 1973). Because the molecular mass of this metabolite was 28 daltons less than that of doxapram, this metabolite was identified tentatively as 4-(2morpholinoethyl)-3,3-diphenyl-2-pyrrolidinone.…”

Section: Urinary Metabolite Identificationmentioning

confidence: 95%

Pharmacokinetics and metabolism of intravenous doxapram in horses

Samś

Detra

Muir

1992

Equine Veterinary Journal

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Summary The pharmacokinetics and metabolism of doxapram in horses administered intravenous (iv) doses of 0.275, 0.55 and 1.1 mg doxapram/kg bodyweight (bwt) were investigated. Plasma doxapram concentrations decreased rapidly after drug administration and the disappearance of doxapram from plasma was best described by a polyexponential equation. Median values of total body clearance were 10.9, 10.6 and 10.9 ml/min/kg bwt for the three doses and were independent of dose. The steady‐state volume of distribution was approximately 1,200 ml/kg bwt and the median biological half‐life ranged from 121 to 178 mins. Plasma protein binding of doxapram ranged from 76.0 to 85.4 per cent. The blood:plasma doxapram concentration ratio was approximately 0.8 and the affinity of the red blood cells for doxapram ranged from 2.0 to 2.8 indicating sequestration of doxapram in erythrocytes. Renal clearance of doxapram was a minor route of elimination. Metabolic clearance of doxapram appeared to be a major route of elimination. Four metabolites of doxapram were isolated from urine and were identified. The metabolites were: a) 1‐ethyl‐4‐[(2‐hydroxyethyl) amino]ethyl‐3,3‐diphenyl‐2‐pyr‐rolidinone, b) a glucuronic acid or sulphuric acid conjugate of 1‐ethyl‐3‐(hydroxyphenyl)‐4‐(2‐morpholinoethyl)‐3‐phenyl‐pyr‐rolidinone, c) 3,3‐diphenyl‐4‐(2‐morpholinoethyl)‐2‐pyr‐rolidinone and d) 1‐(2‐hydroxyethyl)‐3,3‐diphenyl‐4‐(2‐morpholinoethyl)‐2‐pyr‐rolidinone. The rapid disappearance of doxapram from plasma immediately after iv administration was attributed to redistribution of the drug from plasma to other tissues. The short duration of clinical effect from doxapram may be attributed to redistribution of the drug from plasma and other well‐perfused tissues, such as the brain, to less well‐perfused tissues such as the skeletal muscles and adipose tissue. Continuous or repeated administration of doxapram could prolong the duration of clinical effect because re‐distribution is less important as steady‐state conditions are approached.

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“…The morpholine ring of indeloxazine was acylated to produce M-4 from M-2 and oxidized to produce morpholinones M-1 and M-3. Oxidation of the morpholine ring to the corresponding morpholinones has been found to occur in the metabolism of morpholine derivatives, doxapram (Pitts et al 1973), viloxazine , Caseand Reeves 1975), CERM 1841(Kucharczyket al 1979)and M 73101 (Hayashi etal. 1978.…”

Section: Discussionmentioning

confidence: 97%

Disposition and metabolism of indeloxazine hydrochloride, a cerebral activator, in rats

Kamimura¹,

Enjoji²,

Sasaki³

et al. 1987

Xenobiotica

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1. The disposition and metabolism of indeloxazine hydrochloride ((+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride) were studied in male Sprague-Dawley rats. 2. After oral administration of 14C-indeloxazine hydrochloride, the plasma concentration of total radioactivity reached a maximum at 15 min and declined with an apparent half-life of 2.2 h in the first 6 h period and declined more slowly thereafter. Unchanged drug in the plasma represented 13.5%, 5.9% and 0.4% of the total radioactivity at 15 min, 1 h and 6 h respectively after administration and levels decayed with a half-life of 0.9 h. 3. After oral and i.v. administration of the labelled compound, the urinary and faecal excretion of radioactivity in 72 h were 61-65% and 31-36% of the dose, respectively. Biliary excretion in bile duct-cannulated animals amounted to 49% of the dose in 72 h. 4. Seven metabolites have been isolated from the plasma or urine and characterized by i.r., n.m.r. and mass spectrometry. They were derived through dihydrodiol formation in the indene ring, hydroxylation of the indene ring and N-acetylation, oxidation and oxidative degradation of the morpholine ring. Some metabolites were excreted as their glucuronic acid or glucose conjugates. The major metabolite appeared to the trans-indandiol analogue of indeloxazine. 5. Possible metabolic pathways of degradation of the morpholine ring are discussed.

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Identification of Doxapram Metabolites using High Pressure Ion Exchange Chromatography and Mass Spectroscopy

Cited by 28 publications

References 5 publications

Gastrointestinal Absorption of Doxapram in Neonates

Gastrointestinal Absorption of Doxapram in Neonates

Pharmacokinetics and metabolism of intravenous doxapram in horses

Disposition and metabolism of indeloxazine hydrochloride, a cerebral activator, in rats

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