Pharmacokinetics of theophylline and its metabolites in rabbits

Celardo, Antonio; Traina, G. L.; Jankowski, Andrzej; Bonati, Maurizio

doi:10.1007/bf03189755

Cited by 10 publications

(6 citation statements)

References 24 publications

(29 reference statements)

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“…Theophylline concentrations were assayed in plasma by a previously described HPLC method [24], slightly modified. Briefly, speci mens (50-100 pi) were quantified after chloroforrmisopropyl alcohol (75:25 v/v) extraction of I ml of acetic acid (0.5% in water) plus 100 pi of internal standard (10 pg/ml of 8-chlorotheophylline, EGAChemie, Stcinheim, FRG).…”

Section: Methodsmentioning

confidence: 99%

Plasma Protein Binding of Theophylline during Development in the Rabbit

et al. 1991

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The plasma protein binding profile of theophylline was investigated in the rabbit during the perinatal and developmental period. The roles of unbound plasma theophylline fraction (TH_u), albumin, nonesterified fatty acids (NEFA) and plasma bilirubin levels were analyzed. Plasma total protein and albumin levels doubled with age from the 1st day of life to maturity (from 3.1 to 5.3 and 1.6 to 3.7 g/l, respectively). TH_U, NEFA and bilirubin levels were inversely related to age, and decreased from 81 to 37%, 2,136 to 239 μEq/l and 2.4 to 0.20 mg/dl, respectively. A linear correlation was shown between TH_u and albumin, NEFA, and bilirubin plasma concentrations. Stepwise multiple linear regression analysis, including albumin, NEFA and bilirubin values as independent variables, identified NEFA as the variable explaining most of the variability in plasma protein binding of theophylline. Findings support the need for careful interpretation (with a view to therapeutic utilization) of estimates of plasma protein unbound fraction of a drug during development. This fact highlights the importance of considering not only protein but NEFA concentrations too.

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Section: Methodsmentioning

confidence: 99%

Plasma Protein Binding of Theophylline during Development in the Rabbit

et al. 1991

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“…The unbound plasma concentration vs time is shown in Figure 1 and the estimated pharmacokinetic parameters are reported in Table I. When isbufylline was given i.v., a rapid loglinear decline was observed and a mean elimination rate constant of 0.025 min-I was calculated corresponding to an average of 27.3 min half-life, about 100times shorter than that calculated when the same theophylline dose was given to adult rabbits (tl/2 = 4.9 h) (9). After the oral dose, unbound isbufylline plasma concentrations rapidly reached maximum levels of 2.10 J.18Iml (Cmax) at 5 min, then declined with a 0.024 min-I constant rate (elimination half-life of 28.8 min).…”

Section: Resultsmentioning

confidence: 99%

“…After i.v. and oral administration, excretion of isbufylline only amounted to a small percentage of the administered dose (0.10-0.20%) over 48 h, compared to 15% of theophylline that was excreted unchanged (9); this means that isbufylline is almostcompletelymetabolized. Further qualitative and quantitative infonnation on isbufylline metabolism is needed; fmdings reported here for the first time, describeonly the isbufylline kinetic profile in rabbits.…”

Section: Resultsmentioning

confidence: 99%

Bioavailability of oral isbufylline in rabbits

Celardo¹,

Dell’Elba²,

Bonati³

1992

European Journal of Drug Metabolism and Pharmacokinetics

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The bioavailability of isbufylline was assessed in male rabbits given 12 mg/kg i.v. (intravenous) or per os (oral) according to a randomized design. The concentrations of unbound (fu = 54.0) isbufylline were considered in plasma as a function of time, after i.v. and oral administration. After oral administration in saline solution, a mean absolute oral bioavailability of 59.6% was calculated. The drug is rapidly absorbed and the comparison of the kinetic profiles after i.v. and per os administration, revealed a rapid elimination: t1/2 27.3 and 28.8 min respectively, and a total body clearance of 67.06 ml/min/kg. Urinary recovery 0-48 h accounted for less than 1% of the dose.

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“…Theophylline is metabolized in the liver to three major metabolites: 1‐methylxanthine (1‐MX), 3‐methylxanthine (3‐MX) and 1,3‐dimethyluric acid (1,3‐DMU). 1‐MX is further hydroxylated to 1‐methyluric acid (1‐MU) (Celardo et al. , 1985; McManus et al.…”

Section: Introductionmentioning

confidence: 99%

“…Theophylline is metabolized in the liver to three major metabolites: 1-methylxanthine (1-MX), 3-methylxanthine (3-MX) and 1,3-dimethyluric acid (1,3-DMU). 1-MX is further hydroxylated to 1-methyluric acid (1-MU) (Celardo et al, 1985;McManus et al, 1988;Bouraoui et al, 1995). Knowledge about the bio-activity of these metabolites is limited to their convulsive activity in mice (Yamamoto et al, 1996) and in rats (Ramzan & Levy, 1986), as well as to the relaxing activity of 3-MX on the human, cat and guinea-pig airways (Persson & Andersson, 1977;Ogawa et al, 1989;Tanaka et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Theophylline and its metabolites produce a stimulating cholinergic effect on the small intestine and a nonadrenergic noncholinergic relaxing effect on the colon: a comparative study in the rabbit intestine

Psarra¹,

Batzias²,

Peeters³

et al. 2007

Vet Pharm & Therapeutics

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The present study examines comparatively the effects of theophylline and its metabolites, 1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU) along the rabbit intestine, and explores the underlying mechanism(s). In the small intestine, theophylline produces atropine- and hexamethonium-sensitive increases in both the amplitude of phasic contractions and the basal tone. All metabolites mimic the theophylline's stimulating effect. In particular, concerning the phasic contractions, all metabolites are more potent than theophylline in the duodenum and jejunum, while in the ileum, only 1-MU is more potent. Regarding the basal tone, the metabolites show, in most cases, higher efficacy in all small intestinal regions, the maximum effects of 3-MX and 1-MU on the duodenum and ileum being double or triple the one of theophylline. In the ascending colon, while lower concentrations of theophylline produce an atropine- and hexamethonium-sensitive increase in the basal tone, higher ones produce a postsynaptic, nonadrenergic noncholinergic (NANC) relaxing effect. 1-MU mimics, in a weaker manner, theophylline's effect, while the other metabolites produce only relaxation, the potency rank of order being 3-MX>1-MX=1,3-DMU>theophylline. It is suggested that the theophylline and its metabolites stimulatory effect involves a cholinergic pathway, while the relaxing one is due to 3('),5(')-cyclic adenosine monophosphate (cAMP) elevation mediated by the theophylline and its metabolites inhibitory action on phosphodiesterases (PDEs).

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Pharmacokinetics of theophylline and its metabolites in rabbits

Cited by 10 publications

References 24 publications

Plasma Protein Binding of Theophylline during Development in the Rabbit

Plasma Protein Binding of Theophylline during Development in the Rabbit

Bioavailability of oral isbufylline in rabbits

Theophylline and its metabolites produce a stimulating cholinergic effect on the small intestine and a nonadrenergic noncholinergic relaxing effect on the colon: a comparative study in the rabbit intestine

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