Effects of passive smoking on theophylline clearance

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long-term exposure to cigarette smoke, and seven age-matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48-hour postinfusion period. Clearance for passive smokers was 6.01 x 10(-2) L/hr.kg and for nonsmokers, clearance was 4.09 x 10(-2) L/hr.kg (p less than 0.025). Terminal elimination half-life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p less than 0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p less than 0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p less than 0.004) and urine (p less than 0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r = 0.73, p less than 0.01) and urine (r = 0.79, p less than 0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.     

Studies on theophylline metabolism: autoinduction and inhibition by antipyrine

Theophylline metabolism was accelerated in 11 of 13 normal male volunteers who received theophylline for 1 week in usual therapeutic doses (3 mg/kg orally t.i.d.). Mean theophylline clearance increased 24% and mean salivary elimination half-life (t1/2) decreased 16%, whereas the mean apparent volume of distribution of theophylline was unchanged at 0.7 L/kg. Large variations occurred in the extent of autoinduction, ranging from no change in two subjects to doubling of theophylline clearance in two others. Subjects who accelerated their theophylline metabolism exhibited a high inverse correlation between the extent of their induction and their two control values for theophylline clearance (r = -0.88 and -0.91; P less than 0.05). A single oral dose of antipyrine (18 mg/kg) simultaneously coadministered with a single oral dose of theophylline (5 mg/kg) retarded the metabolism of both theophylline and antipyrine. No significant change occurred in the apparent volume of distribution of either drug. Coadministration with antipyrine reduced mean theophylline clearance 18% and increased salivary t1/2 39%. Theophylline decreased mean antipyrine clearance 21% and increased its mean salivary t1/2 28%. Theophylline metabolism, therefore, is sensitive to not only autoinduction when theophylline is given long term at usual therapeutic doses but also inhibition when theophylline is coadministered with certain drugs.     

Cigarette smoking and theophylline metabolism: effects of cimetidine

The inhibition of theophylline metabolism by cimetidine was investigated in young male cigarette smokers (greater than 20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) over days 1 to 7 or 8 to 14. On days 7 and 14, a tracer dose (10 mg) of stable isotope-labeled theophylline was injected intravenously with the oral dose of theophylline. Serial plasma samples were then obtained for 24 hours and both molecular forms of theophylline were assayed by mass spectrometry after purification by HPLC. Theophylline bioavailability, volume of distribution, and protein binding were of the same order in both groups and were not affected by cimetidine. Although the basal theophylline elimination rate constant was 46% greater and clearance was 54% greater in smokers than in nonsmokers, the proportionate changes in steady-state plasma concentrations, t1/2, and clearance due to cimetidine were much the same in both groups. Plasma thiocyanate concentrations were higher in smokers than in nonsmokers and were related to theophylline clearance. Our findings indicate that cimetidine inhibits theophylline metabolism to a similar extent in both smokers and nonsmokers. Determination of plasma thiocyanate levels may be valuable in the prediction of theophylline clearance.     

Effects of dietary protein on theophylline pharmacokinetics and caffeine and aminopyrine breath tests

The effects of low- and high-protein diets on theophylline kinetics and the time course of changes in 13C-labeled caffeine and aminopyrine CO2 breath tests were examined in six young men. With a low-protein diet, mean theophylline clearance fell 21% (P less than 0.04) and the t1/2 rose from 8.0 to 10.6 hours (P less than 0.02). With a high-protein diet, mean theophylline clearance rose 26% (P less than 0.004) and the t1/2 shortened to 7.4 hours (P less than 0.03). Theophylline volume of distribution and protein binding did not change. Renal clearance of theophylline was lowered during the low-protein diet. Theophylline clearance correlated with caffeine breath test values during the low- (r = 0.73) and high- (r = 0.70) protein diets. Theophylline clearance correlated less well with the aminopyrine breath test values during the low- (r = 0.47) and high- (r = 0.55) protein diets. Thus dietary protein significantly influenced theophylline clearance, but the caffeine and aminopyrine breath tests showed a differential response to this important environmental factor.     

Inhibition of theophylline clearance by coadministered ofloxacin without alteration of theophylline effects.

The influence of multiple doses of ofloxacin (ORF 18489) on the disposition of theophylline was studied in 15 male volunteers. Subjects were confined in the Clinical Research Unit for 13 days and given a xanthine-free diet. A single dose (3 mg/kg) of theophylline was given orally, and blood samples were collected at fixed time intervals for 36 h. The concentrations of theophylline were measured with TDX (Abbott Diagnostics, Irving, Tex.), and clearance was calculated. Theophylline clearance was used to individualize subsequent doses to achieve average steady-state theophylline concentrations in plasma of 10 mg/liter. Individualized theophylline doses were administered every 8 h until steady-state conditions were reached. Theophylline clearance was determined again at steady state and on days 7 and 8. On day 8, ofloxacin (400 mg every 12 h) was given concomitantly with theophylline. Theophylline clearance was measured again on day 12, after the last theophylline dose. Administration of ofloxacin for 1 day did not change theophylline clearance, but coadministration for 4 days significantly decreased theophylline clearance by 12.1% (P less than 0.05). The area under the concentration-time curve for theophylline increased 9.9% (P less than 0.05), and average steady-state concentrations in plasma increased 10.3% (P less than 0.05). Despite changes in clearance, adverse effects of theophylline did not increase during coadministration of ofloxacin. Although statistically significant, the interaction between ofloxacin and theophylline is unlikely to be of major clinical importance.     

Theophylline pharmacokinetics in normal elderly subjects

The effect of age on theophylline kinetics was examined in six normal young men and six elderly men. There were no age-associated differences in theophylline volume of distribution, total clearance, or t1/2. The unbound fraction of theophylline was significantly raised in the elderly (mean 77.7% vs. 62.3%, p less than 0.001) and was correlated with the serum albumin level (r = -0.7, p less than 0.01). Theophylline nonrenal clearance was not changed, but the total unbound clearance was significantly reduced in the elderly subjects as compared with the young ones (mean 0.744 vs. 1.085 ml/min/kg, p less than 0.05). Creatinine clearance was reduced in the elderly and was significantly correlated with unbound renal clearance (r = 0.6, p less than 0.04). There were no age-related differences in the urinary excretion of theophylline, 1-methyluric acid, 3-methylxanthine, or 1,3-dimethyluric acid. However, significant reduction in unbound renal theophylline clearance (p less than 0.002) as well as the unbound metabolic clearance of 1,3-dimethyluric acid (p less than 0.03), 3-methylxanthine (p less than 0.04), and 1-methyluric acid (p less than 0.02) were observed in the elderly subjects. These observations indicate that both renal and metabolic elimination processes for theophylline are less active in the normal elderly.     

Cigarette smoking and theophylline metabolism: effects of phenytoin

The induction of theophylline clearance by phenytoin was investigated in 12 young male subjects (six nonsmokers and six cigarette smokers). Each subject received intravenous theophylline to determine baseline pharmacokinetics. This was followed by an intravenous loading dose of phenytoin sodium and oral maintenance dosing for 2 weeks, after which the intravenous theophylline study was repeated. Phenytoin concentrations were similar in nonsmokers (10.8 +/- 2.0 micrograms/ml) and smokers (11.5 +/- 0.9 micrograms/ml). Control theophylline elimination half-life was 35% less and clearance 88% greater in smokers than in nonsmokers. The proportionate changes in half-life (26.8% +/- 5.6% in smokers and 25.8% +/- 3.5% in nonsmokers) and clearance (48.0% +/- 10.1% in smokers and 39.7% +/- 7.2% in nonsmokers) as the result of phenytoin induction were similar in both groups. These results demonstrate that the induction of theophylline clearance by phenytoin is additive to that caused by cigarette smoking and provide support for the suggestion that theophylline metabolism is influenced by multiple polymorphisms.     

Assessment of caffeine exposure: caffeine content of beverages, caffeine intake, and plasma concentrations of methylxanthines

The caffeine content of all tea or coffee beverages consumed by 17 healthy adults over 24 hours was measured. Plasma caffeine, theophylline, theobromine, and paraxanthine concentrations were determined over the same 24 hours. The average caffeine content per drink was 60.4 +/- 21.8 mg for instant coffee (14-fold range), 80.1 +/- 19.2 mg for brewed coffee (2.8-fold range), and 28.8 +/- 13.7 mg for tea (5.5-fold range). The number of drinks of coffee and tea consumed was a poor index of actual caffeine intake (r2 = 0.42). Caffeine intake correlated poorly with the 24-hour average caffeine concentration (r2 = 0.41), but there was a very good correlation between a single plasma caffeine concentration measured at 5 PM and the 24-hour average concentration (r2 = 0.94). The same was true for paraxanthine (r2 = 0.86). Paraxanthine accounted for 67.3% of the total dimethylxanthines in plasma, while theobromine and theophylline accounted for 24.4% and 8.3%, respectively. Mean caffeine clearance was 1.2 +/- 0.3 ml/min/kg. Plasma caffeine concentration before the first drink in the morning correlated very poorly with caffeine clearance (r2 = 0.07), even when adjusted for caffeine intake (r2 = 0.21).     

Theophylline disposition in tetraplegic man

We studied the time-course of serum theophylline concentration after a 30-minute intravenous infusion of aminophylline (6 mg/kg) in 18 traumatic tetraplegic (nine smoking, nine nonsmoking) and in six control (nonsmoking) subjects. All study subjects were healthy men with normal renal function. Pharmacokinetic parameters were calculated from a linear regression analysis of the terminal log-linear portion of the log serum theophylline concentration-time curves. The terminal elimination kinetics of theophylline in this study were best characterized by first order elimination from a one compartment-open model. A statistically significant difference (P less than .05) was demonstrated between the means and variances of theophylline clearance (Cl ml/kg/min) and hours of half-life (t1/2) for control subjects and smoking tetraplegics. Total body clearance of theophylline was greater in all tetraplegic subjects, the greatest difference in total clearance of theophylline adjusted to body weight being observed between tetraplegic smokers and nonsmoking controls with an intact central nervous system (P less than .05). Theophylline volume of distribution (Vdarea) did not differ significantly from Vdarea in able-bodied subjects. Tetraplegic individuals have multiple disorders and marked pharmacokinetic variation, which might be expected to make serum concentration and toxicity of theophylline unpredictable using population averages.     

Impact of ciprofloxacin on theophylline clearance and steady-state concentrations in serum.

The effect of a multiple-dose regimen of oral ciprofloxacin (750 mg every 12 h for 11 doses) on the clearance and steady-state concentrations of theophylline in trough (predose) serum was evaluated in nine healthy male subjects, each serving as his own control. Theophylline was taken as a sustained release tablet per os in a dose of 200 mg every 12 h for 19 doses. Theophylline concentrations in serum were measured immediately before each theophylline dose. Ciprofloxacin was administered on study day 4 through the first dose of study day 8. Theophylline concentrations in serum were also measured on study days 3, 6, 8, and 10 at the following times after the first dose of each day: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 10, and 12 h. Steady-state theophylline concentrations in trough serum were significantly higher during ciprofloxacin treatment (day 8) than before (day 3) or after (day 10) ciprofloxacin administration (P less than 0.01). Likewise, theophylline clearance was significantly slower (P less than 0.01) during ciprofloxacin treatment (day 8) than before it (day 3) or after it (day 10). The magnitude of ciprofloxacin-induced changes was approximately 30%. These results suggest that a multidose regimen of ciprofloxacin significantly slows the clearance of theophylline and elevates theophylline concentrations in serum.     

Cystic fibrosis: enhanced theophylline metabolism may be linked to the disease

Theophylline disposition (5.5 mg/kg administered intravenously) was studied in 12 patients with cystic fibrosis (CF) and 16 healthy control volunteers. Dietary controls and logs were used to minimize the influence of food on theophylline metabolism. Control subjects were restudied in random order on two subsequent occasions after 2 weeks of either pancreatic enzymes or placebo. Theophylline and its three main metabolites, 1-methyluric acid, 3-methylxanthine, and 1,3-dimethyluric acid, were analyzed in serum and urine by HPLC. The total body clearance, renal clearance, nonrenal clearance, and volume of distribution of theophylline were significantly greater (p less than 0.05) in patients with CF than in control subjects. The increased nonrenal clearance was the result of increased biotransformation to each of the three main metabolites. Patients with CF exhibited enhanced N-demethylation and 8-hydroxylation of theophylline, pathways that appear to be mediated by two different families of P-450 enzymes. Theophylline clearance after 2 weeks of pancreatic enzyme administration in the control subjects was the same as with placebo. Possible reasons for enhanced theophylline biotransformation in CF are discussed.     

Safety of fleroxacin coadministered with theophylline to young and elderly volunteers.

The influence of multiple doses of fleroxacin on the plasma clearance and the urinary excretion of theophylline was studied in 19 young and 18 elderly male volunteers. A theophylline dosage individualized to obtain a mean theophylline concentration in plasma of 10 +/- 3 micrograms/ml was administered for 1 week to each subject. At week 2, oral fleroxacin (400 mg once daily) was added. Theophylline concentrations in plasma were measured with TDx (Abbott Diagnostics, Mississauga, Ontario, Canada), and urinary excretion of theophylline and its three major metabolites was measured by high-performance liquid chromatography. Total theophylline clearance remained essentially unchanged throughout the study period (3.5 and 2.9 liters/h in the young and the elderly, respectively) both after a single fleroxacin dose and after multiple doses. Although significant changes occurred in the urinary excretion of unchanged theophylline and its metabolites after a single fleroxacin dose, no changes were observed after multiple doses. Side effects consisted mainly of gastrointestinal and sleep disturbances, more related to theophylline; photosensitivity was observed in six subjects and was attributed to fleroxacin. We conclude that fleroxacin may be administered concomitantly with theophylline in either young or elderly patients. Close monitoring of theophylline concentrations in serum should be performed, particularly in patients with chronic obstructive pulmonary disease, for whom data are currently lacking.     

Effect of norfloxacin on theophylline pharmacokinetics at steady state.

Norfloxacin is a currently marketed fluoroquinolone antibiotic. Other quinolones which are structurally similar to norfloxacin, particularly enoxacin, inhibit theophylline clearance. Since norfloxacin may be administered to patients also receiving theophylline, we studied the effect of norfloxacin on the pharmacokinetics of theophylline in 10 healthy male volunteers. A randomized, crossover study design with a 2-week washout period between treatments was used. Subjects received oral theophylline (200 mg of aminophylline [theophylline ethylenediamine]) three times daily for 4 days either alone or with 400 mg of norfloxacin (orally) twice daily for the same period. Theophylline concentrations in serum were significantly higher (P less than 0.05) at 0, 3, 4, 10, and 12 h following the final dose in the norfloxacin treatment group than in the group receiving only theophylline. However, mean theophylline oral clearance was not significantly different between the two treatments (2.85 +/- 0.68 liters/h without norfloxacin versus 2.56 +/- 0.53 liters/h with norfloxacin [P = 0.08]). Similarly, no significant differences were observed in theophylline half-life (P = 0.11). We conclude that norfloxacin is unlikely to have a clinically significant effect on theophylline disposition in most patients.     

Effect of lomefloxacin on theophylline pharmacokinetics.

A study involving 25 health male volunteers was conducted to evaluate the effect of lomefloxacin on the pharmacokinetics of theophylline. The mean age was 22.4 +/- 3.0 years, and the mean weight was 77.3 +/- 7.7 kg. A single 6-mg/kg aminophylline dose was given intravenously on study days 1 and 15. The subjects received a 400-mg lomefloxacin dose (four 100-mg capsules) on study days 9 through 15. No treatment was given on study days 2 through 8. Thirteen blood samples were collected within 24 h after each aminophylline dose. Theophylline concentrations in serum were measured by enzyme immunoassay (EMIT). The mean aminophylline dose was 437 +/- 36 mg, equivalent to 344 mg of theophylline. Multiple doses of lomefloxacin had no effect on the area under the concentration-time curve from 0 h to infinity, maximal concentration, or clearance of theophylline from serum. There was a slight increase in the theophylline half-life from 6.72 +/- 1.63 to 7.02 +/- 1.37 h after lomefloxacin dosing (P = 0.04); however, the change was clinically insignificant. No change in theophylline dose is required when lomefloxacin therapy is instituted in a patient receiving theophylline.     

Secretion of Thyroxine and Non-Thyroxine Iodine by the Normal Human Thyroid Gland. Influence of Carbimazole and Pharmacological Doses of Iodide

Abstract. In order to measure the effect of antithyroid agents on thyroxine and non-thyroxine iodine secretion by the normal human thyroid gland, 12 normal persons were given tracer amounts of iodide-¹²⁵I. 7 to 11 days later thyroxine-¹³¹I was injected I.V. Two days later the following serial measurements were started: Serum protein-bound labeled iodine (PB¹²⁵ PB¹³¹I), serum total thyroxine, and excretion of ¹²⁵I and ¹³¹I in urine.–In the control period (no drugs) the secretion rate for thyroxine was 83 μg/day. Carbimazole (15 mg three times daily) for 6 days did not affect thyroxine secretion despite a complete block of iodine uptake by the thyroid. Non-thyroxine iodine secretion was 59 μg/day in the control period and rose to 183 μg under carbimazole.–Non-thyroxine iodine includes triiodothyronine and any non-hormonal iodine, such as iodide derived from the deiodination of iodotyrosines, secreted by the gland. Based on recently published estimates it was assumed that the triiodothyronine contribution was not more than 24 μg. This left a considerable efflux of non-hormonal iodine even in the control period. Most of the non-hormonal iodine produced, however, was recycled into thyroglobulin without leaving the gland. After blocking reutilization by carbimazole large amounts of non-hormonal iodine were secreted by the gland. High doses of iodide (30 mg three times daily) in combination with carbimazole led to a rapid 45% decline in thyroxine secretion. Since a complete block of hormone synthesis by carbimazole alone had no such effect, high iodide doses must act at a different site, presumably by slowing down the release of hormone from preformed thyroglobulin stores. The findings indicate that carbimazole enhances the sensitivity of the normal thyroid gland toward pharmacological doses of iodide.–High doses of iodide together with carbimazole reduced the secretion of non-hormonal iodine (which can be taken as an index of thyroglobulin hydrolysis) by only 31%. Moreover some subjects showed no reduction at all, despite of concomitant fall in hormone secretion. The lack of correlation between the decreases of thyroxine and of non-hormonal iodine secretion does not support the generally held view that high doses of iodide block hormone release by interfering with the hydrolysis of thyroglobulin.     

Determination of theophylline in saliva, using fluorescence polarization immunoassay (FPIA)

Theophylline concentrations were determined by fluorescence polarization immunoassay (FPIA) in saliva, serum and serum water of healthy volunteers and outpatients after administration of single theophylline doses, and after the administration of several doses in order to establish a steady state. The FPIA allowed rapid and reliable theophylline determinations in saliva and serum water (between-days coefficients of variation: less than 3%; recovery: 95-03%). Salivary theophylline concentrations measured by FPIA in 30 samples agreed well with those determined by HPLC. Furthermore the results obtained by ultrafiltration for the concentration of unbound theophylline in serum water were in good agreement with those determined by ultracentrifugation. The binding of theophylline by serum protein rose by about 25%, when the pH of the samples was increased from 7.0 to 8.0. After adjusting the pH to 7.4, average values for theophylline binding to proteins at 25 degrees C ranged from 48.5 to 52.2% in serum samples from outpatients and healthy adults. Salivary theophylline concentrations correlated well with total and free serum theophylline concentrations in healthy adults and outpatients (r = 0.90-0.98). The theophylline concentration in saliva was on average about 20-30% higher than the unbound theophylline concentration in serum water. The saliva/serum concentration ratio of theophylline showed some intersubject variation (0.68 +/- 0.08; range: 0.50-0.85). Using the mean saliva/serum concentration ratio of the patient group, steady state serum theophylline concentrations were predicted from salivary levels with a mean error of 7.6% (range: 0.0-26.8%). The salivary theophylline concentration appears to be a suitable parameter for assessment of compliance, for identification of patients with inappropriate dosage, and for consequent dosage adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aging and drug interactions. II. Effect of phenytoin and smoking on the oxidation of theophylline and cortisol in healthy men

The effect of age on the induction of theophylline metabolism by phenytoin was examined in healthy young and old male cigarette smokers (greater than or equal to 20 cigarettes/day) and nonsmokers. Two single dose studies of theophylline pharmacokinetics were performed, one as a base-line control and another after a 2-week course of phenytoin. Phenytoin was administered as an i.v. loading dose followed by oral ingestion. The dose was adjusted to achieve total phenytoin plasma concentrations within a low therapeutic range (10-13 micrograms/ml). Free phenytoin concentrations in plasma were slightly higher in old (nonsmokers 0.84 +/- 0.13 micrograms/ml; smokers 0.89 +/- 0.12 micrograms/ml) than in young (nonsmokers 0.75 +/- 0.10 micrograms/ml; smokers 0.72 +/- 0.10 micrograms/ml) subjects, but the differences were not significant. Base-line plasma theophylline clearance was 30% lower in old compared with young nonsmokers (34.0 +/- 2.5 vs. 48.8 +/- 2.6 ml/hr/kg, P less than .001), whereas the small age difference between old and young smokers (86.0 +/- 8.4 vs. 72.4 +/- 8.0 ml/hr/kg) was not significant. Smokers had higher values of theophylline clearance than nonsmokers regardless of age. Half-life was prolonged in old nonsmokers in proportion to decreased clearance, despite a slight decrease in volume of distribution. Phenytoin induced theophylline metabolism to an equal degree in both age groups and in both smokers (young 42.6 +/- 6.5%; old 47.3 +/- 3.6%) and nonsmokers (young 56.3 +/- 8.8%; old 45.4 +/- 6.4%). The magnitude of its induction in smokers was additive to that of cigarette smoking. Old age was associated with a modest selective reduction in N-demethylated metabolic pathways to 3-methylxanthine and 1-methyluric acid, whereas smoking preferentially induced the formation of these products. Phenytoin increased the production of all theophylline primary metabolites to an equal degree in both old and young subjects. The urinary excretion of 6 beta-hydroxycortisol was not influenced significantly by age or smoking and increased 2- to 3-fold in all subject groups with phenytoin. These results confirm earlier observations of a reduction in basal oxidative capacity in elderly nonsmoking males. They also demonstrate that the ability to induce the metabolism of theophylline by smoking or phenytoin and the ability to induce the metabolism of cortisol by phenytoin are maintained in old age.     

Aging and drug interactions. I. Effect of cimetidine and smoking on the oxidation of theophylline and cortisol in healthy men

The effect of age on the inhibition of theophylline metabolism was investigated in young and old male cigarette smokers (greater than 20 cigarettes/day) and nonsmokers by stable isotope methodology. Subjects received oral theophylline (510 mg/day) for 14 days and cimetidine (1200 mg/day) during days 1 to 7 or 8 to 14. On days 7 and 14, a tracer dose (10 mg i.v.) of stable isotope-labeled theophylline was administered with the oral dose of theophylline. Plasma clearance in old nonsmokers was 33% less than in young nonsmokers. Values in both young and old smokers were not significantly different but exceeded those in non-smokers. Because volume of distribution was similar in all groups, the half-lives were prolonged in proportion to the decrease in clearance. Although smoking was associated with selective induction of the formation of 3-methylxanthine and 1-methyluric acid, the effect of cimetidine was nonselective and the proportionate inhibitory effects of cimetidine on theophylline metabolism did not differ with age or smoking status. The excretion of 6 beta-hydroxycortisol was similar in smokers and non-smokers but was slightly inhibited by cimetidine. Cimetidine also reduced the interindividual variation in the absorption of theophylline. Despite a reduction in the basal oxidative capacity in healthy male nonsmokers, these results indicate that both the induction of theophylline metabolism by smoking and the inhibition of theophylline metabolism by cimetidine are preserved in old age.     

CLINICAL EVALUATION OF THEOPHYLLINE BINDING TO PLASMA PROTEIN IN BRONCHIAL ASTHMATIC PATIENTS

Theophylline binding to plasma protein was studied with seven bronchial asthmatic inpatients. The extent of protein binding was monitored using an ultrafiltration device, EMIT® FreeLevel_TM System 1, whose performance is pH independent between 7·5 and 8·5 and concentration independent between 2 and 10 mcg/ml. When protein-free theophylline solutions are used a linear pH dependency was observed between 7·0 and 8.3. With theophylline-spiked human plasma using the same samples, the binding was found to be concentration-independent in the range 5 to 40 mcg/ml. The intra- and inter-individual variations in theophylline binding to plasma proteins were relatively large. A calculation procedure for predicting free fractions at normal physiological plasma pH, 7.4, using the observed free fraction at a given plasma pH is proposed. A good correlation was obtained between plasma and salivary theophylline concentrations. Salivary levels alone, however, are unreliable for monitoring theophylline therapy.     

Evaluation of a novel Bayesian method for individualizing theophylline dosage

A novel Bayesian drug dosing program (Abbott Pharmacokinetic Systems, Theophylline Program) was evaluated. The predictive accuracy of this method was assessed in 10 healthy volunteers receiving single intravenous test doses. Estimates for clearance and distribution volume were compared with those obtained from the area under the curve. The observed prediction error depended largely on sampling time. The deviations were lowest for the distribution volume during the first 60 min and for clearance at 12 hours after theophylline administration. Furthermore the Bayesian technique was prospectively evaluated in 10 hospitalized and 22 outpatients treated with sustained-release theophylline preparations (Uniphyllin, Bronchoretard, PulmiDur). Predictive precision and accuracy were adequate, if theophylline was given twice daily. The highest predictive accuracy was achieved in outpatients, if predictions were based on trough concentrations. In 19/22 outpatients prediction errors were within a clinically acceptable range (mean prediction error +/- standard deviation; -0.6 +/- 2.1 mg/l). Moreover in hospitalized patients (n = 5) with twice-daily maintenance regimens, concentration-time curves could mainly be predicted with sufficient accuracy. Hospitalized patients (n = 5) with once-daily dosing showed large fluctuations between peak and trough theophylline concentrations in serum. In these patients a reliable prediction of the concentration-time curves was not possible apparently due to non-linearity of theophylline kinetics. Relatively large prediction errors were found in one patient with acute viral respiratory illness and 3 patients with altered absorption. Despite certain limitations the clinical application of the Bayesian forecasting method tested appears to be promising.