Pharmacokinetics of intravenous theophylline

Mitenko, Paul A.; Ogilvie, Richard I.

doi:10.1002/cpt1973144part1509

Cited by 177 publications

(48 citation statements)

References 2 publications

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“…The disposition parameters of theophylline after intravenous administration in human, which were used as a weight function in the convolution analysis, were data of 24 subjects cited from literatures. [57][58][59] The subjects consist of not only normal volunteers but also asthmatic subjects. But the authors showed that the pharmacokinetic parameters in the group of asthmatic subjects were not significantly different from those in the group of normal volunteers.…”

mentioning

confidence: 99%

Gastrointestinal Transit and Drug Absorption

Kimura

Higaki

2002

Biological & Pharmaceutical Bulletin

173

114

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Oral drug administration is the most convenient and common for drug therapy and it is, therefore, very important and useful to estimate the absorbability of drugs and to predict the plasma concentration profile of drugs after oral administration for the development of novel drugs and/or novel dosage form and the designation of the dosage regimen. Generally, the absorbability of drugs has been estimated by in-situ recirculation studies, in-situ closed loop studies or the analysis by the simple compartment model. The information which can be obtained from these approaches is usually an absorption rate constant, ka. The ka value is generally the averaged one throughout the intestinal tract. However, there is the site-difference in drug absorbability [1][2][3][4] and variable residence time of drugs in each segment must make the contribution of each segment to drug absorption changed, resulting in the different absorbability as a whole. As for the drug absorption after oral administration, the gastrointestinal (GI) transit of a drug is also an important factor to determine the drug absorption and is so variable, as was influenced by not only individual differences, 5) but also the dosage conditions like meals, 6) disease states 7) and so on. Therefore, the absorbability and the residence time in each segment are the major determining factors for drug absorption after oral administration and very important for the analysis of drug absorption kinetics and the estimation of, and the prediction of plasma concentration profiles of drugs. However, the analysis and the estimation of drug absorption after oral administration have been usually performed by a simple compartment model, where even a process of gastric emptying is not included often. This kind of simple model cannot describe the irregular shape in the plasma concentration, which is often observed. Therefore, several models were proposed to analyze the plasma profile, [8][9][10][11] but they are not necessarily based on the practical phenomena, i.e. GI transit and site-different drug absorbability.We have developed a GI-Transit-Absorption (GITA) Model containing the GI transit and absorption processes to analyze and predict the plasma concentration profile after oral administration of aqueous drug solution.12) Although several efficient methods to estimate the absorption of orally administered drug by analyzing the GI disposition following oral administration (GI disposition analysis) have been reported, some are only focused on the gastric emptying based on a model having a stomach and an intestine compartment. 13,14) The other one estimated the intestinal transit of a drug using polyethylene glycol 4000 as a nonabsorbable marker, 10) but the actual data of intestinal transit were not utilized enough to analyze and predict the drug absorption kinetics. Although the analytical procedures for plasma profile of a drug absorbed from successive absorption sites along the GI tract have been also reported, [16][17][18] they just showed the concept and/or simulation stu...

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confidence: 99%

Gastrointestinal Transit and Drug Absorption

Kimura

Higaki

2002

Biological & Pharmaceutical Bulletin

173

114

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“…our results could indicate that caffeine oxidation over N-demethylation, involving lower activity of the cytochrome P-450 monooxygenase system during the first month of life than in older infants or adults compared to data reported in literature for other drugs. Our results suggest different forms of enzymes are involved in these reactions.Since its introduction in the treatment of apnea the disposition of theophylline (T) has been well described, not only in children (18)(19)(20)32) and adults (10, 11,13,15,16,22,26,29,30,31), but also in the premature neonate. Newborns eliminate the drug very slowly (4,12,17,23,28) partially methylating it to caffeine (C) (7-9).…”

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Theophylline Metabolism during the First Month of Life and Development

et al. 1981

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Summary dose of 5.5 mg/kg of T IV followed by maintenance IV doses ofThe metabolic pathway of theophylline (T) was studied in 12 newborns, one young infant, six children, and three adult volunteers. T was injected IV, and blood and urine samples were assayed for T, caffeine (C), and their metabolites by a high-pressure liquid chromatography technique. We confirmed the methylation of T to C in newborn infants but not in older subjects. Demethylation of T to Imethylxanthine was found in the young infant, in children, and in adults, but not in newborns. The major products excreted by neonates were T, 1-methyluric acid, and 1.3-dimethyluric acid. Children excreted a larger fraction of methyluric acids than adults.Renal and body clearance of T and C are reported and discussed in relation to the age. SpeculationOn the grounds of blood and urine samples from subjects treated with theovvlline. our results could indicate that caffeine oxidation over N-demethylation, involving lower activity of the cytochrome P-450 monooxygenase system during the first month of life than in older infants or adults compared to data reported in literature for other drugs. Our results suggest different forms of enzymes are involved in these reactions.Since its introduction in the treatment of apnea the disposition of theophylline (T) has been well described, not only in children (18)(19)(20)32) and adults (10, 11,13,15,16,22,26,29,30,31), but also in the premature neonate. Newborns eliminate the drug very slowly (4,12,17,23,28) partially methylating it to caffeine (C) (7-9). a unique example of drug methylation in humans.T is metabolized in the liver by the P-450-dependent microsomal system, which has been shown to be deficient in the newborn, in relation to several substrates (25).Methylxanthine metabolism has been studied in the adult (5. l I, 15, 29-3 1 ) but except for the paper by Aldridge et al. (I ) on caffeine no data have been published so far on children and neonates. This study was undertaken to: (1) further study the unusual metabolism of T to C; (2) define the metabolic pattern of T in neonates; (3) describe progressive changes of T metabolism during development.

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“…A significantly lower total body clearance of theophylline was also established in the patients with COPD plus CP. The combination of COPD and CP was associated with an average decrease in clearance to 38% of that observed in a selected normal series (Mitenko & Ogilvie, 1973). In light of these findings, it would seem prudent to appropriately adjust oral and intravenous maintenance doses of theophylline in the present of these clinical diagnosis, and to individualize dosage regimens by serum theophylline assays.…”

Section: Pooled Oral and Intravenous Resultsmentioning

confidence: 84%

Impaired theophylline clearance in patients with cor pulmonale.

Vicuna¹,

McNay²,

Ludden³

et al. 1979

Brit J Clinical Pharma

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I The relationship between serum theophylline concentration and daily dose was studied in 45 patients receiving aminophylline orally and in 36 patients receiving it by constant intravenous infusion. 2 Patients were categorized as uncomplicated chronic obstructive pulmonary disease (COPD) or COPD with cor pulmonale (CP). 3 Serum theophylline concentration relative to daily theophylline dose was significantly higher in patients with COPD plus CP than in patients with COPD alone. 4 Total body clearance of theophylline estimated from data obtained during constant intravenous infusion was significantly lower in COPD plus CP than in patients with COPD alone. 5 We conclude that reduced maintenance doses of theophylline are indicated in patients with COPD when complicated with CP.

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Pharmacokinetics of intravenous theophylline

Cited by 177 publications

References 2 publications

Gastrointestinal Transit and Drug Absorption

Gastrointestinal Transit and Drug Absorption

Theophylline Metabolism during the First Month of Life and Development

Impaired theophylline clearance in patients with cor pulmonale.

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