Pharmacokinetic analysis of the effect of the ophylline on pulmonary function in asthmatic children

Levy, Gerhard; Koysooko, Renu

doi:10.1016/s0022-3476(75)80374-x

Cited by 136 publications

(38 citation statements)

References 7 publications

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“…Other studies in patients with chronic, stable airways obstruction have shown a similar dose-response pattern to large doses of /3-adrenoceptor agonist by inhalation (Svedmyr, Malmberg & Thiringer, 1972;Martin et al, 1977;. Shenfield & Paterson (1973) (Jenne, Wyze, Rood & MacDonald, 1972;Mitenko & Ogilvie, 1973;Levy & Koysooko, 1975;Ogilvie, 1978;Weinberger, 1978). This work suggests that salbutamol by inhalation possesses a greater potential therapeutic range with a wider margin of safety than oral theophylline.…”

supporting

confidence: 55%

Dose‐titration comparison of inhaled salbutamol and oral theophylline in asthma.

Marlin¹,

Harris²,

Klumpp³

et al. 1979

Brit J Clinical Pharma

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supporting

confidence: 55%

Dose‐titration comparison of inhaled salbutamol and oral theophylline in asthma.

Marlin¹,

Harris²,

Klumpp³

et al. 1979

Brit J Clinical Pharma

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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).…”

mentioning

confidence: 99%

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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“…Although log-linear decay of theophylline plasma concentration after a single dose have been interpreted to favor the concept of linear kinetics (7,14,(17)(18)(19) dose dependent kinetics of the drug in the therapeutic dose range have been suggested by several innvestigators (2,(8)(9)(10)(11)(12)(20)(21)(22). The finding of dose dependent kinetics was explained by constant excretion rate of 3-MX and 1-MU for some hours after a single oral doe of theophylline (2,12).…”

Section: Discussionmentioning

confidence: 99%

Dose dependent pharmacokinetics of theophylline: Michaelis-menten parameters for its major metabolic pathways

Dadashzadeh

Tajerzaden

2001

Eur. J. Drug Metab. Pharmacokinet.

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Dose Dependency for pharmacokinetics of theophylline and the formation of its major metabolites, 3-methylxanthine (3-MX); 1-methyluric acid (1-MU); 1,3-dimethyluric acid (DMU), were examined by administering three single oral doses (250, 375, 500 mg) of theophylline to six healthy adult volunteers. The serum and urine concentrations of theophylline and the metabolites in serum and urine were determined by high-performance liquid chromatography. Total clearance of theophylline decreased and its half life increased over the range of doses administered (p<0.01). There was a significant dose related decrease in the fractional recovery of 3-MX and 1-MU (p<0.001) and a dose related increase in fractional excretion of DMU and unchanged theophylline (p<0.01 and p<0.001 respectively). No significant dose related changes were observed in the renal clearance of 3-MX, 1-MU and DMU, indicating linear urinary excretion kinetics of the metabolites. Theophylline metabolic clearance to 3-MX as well as to 1-MU decreased with increasing dose but clearance to DMU remained unnaffected by the size of dose. The individual Michaelis-Menten parameters Km and Vmax were estimated for six subjects receiving three different single doses. The Km values for theophylline metabolism to 3-MX, 1-MU and DMU were 2.4+/-0.6, 5.1+/-1.8+/- and 112.3+/-36.8 mg/L respectively and the Vmax values were 3.5+/-0.7, 7.5+/-2.6 and 112.3+/-36.8 mg/hr respectively. The Km values for the N-demethylation pathways (3MX and 1-MU) were lower corresponding to therapeutic serum concentrations of drug. These results suggest that the elimination kinetics of theophylline is nonlinear in the human in the therapeutic range of serum concenntrations and can be explained by saturable formation kinetics of 3-MX and 1-MU. In contrast to previous studies we didn't find obvious indication for nonlinear formation of DMU at therapeutic concentration range.

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Pharmacokinetic analysis of the effect of the ophylline on pulmonary function in asthmatic children

Cited by 136 publications

References 7 publications

Dose‐titration comparison of inhaled salbutamol and oral theophylline in asthma.

Dose‐titration comparison of inhaled salbutamol and oral theophylline in asthma.

Theophylline Metabolism during the First Month of Life and Development

Dose dependent pharmacokinetics of theophylline: Michaelis-menten parameters for its major metabolic pathways

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