The effects of erythromycin on the absorption and disposition kinetics of theophylline

Summary The effects of erythromycin on the kinetics of theophylline were investigated in eight female patients with documented asthma in a crossover study. Theophylline pharmacokinetics were determined at steady state before and after one-week treatment with erythromycin stearate 250 mg given four times a day. Multiple serum samples were collected for 12 h after an aminophylline dose in the two drug treatment phases and assayed by high performance liquid chromatography. The resultant serum theophylline concentration-time data were analyzed by weighted, nonlinear regression analysis to obtain various pharmacokinetic parameters. In this study, the elimination half-live increased from 7.8±1.7 h on the control day to 9.5±1.4 h following treatment with the antibiotic (p<0.02). The estimated apparent volume of distribution for theophylline (V/F) was also observed to increase from 0.42±0.09 l/kg before treatment with erythromycin to 0.53±0.15 l/kg after antibiotic treatment (0.05<p<0.10). In this study, no difference was demonstrated in the apparent clearance rate (Cl_app), apparent first-order absorption rate constant (k_a), maximum serum drug concentration (C_max), time of maximum drug concentration (T_max) or absorption lag time (t_lag) for theophylline before and after treatment with erythromycin. With no apparent alteration in theophylline clearance following erythromycin coadministration, the decrease in the first-order elimination rate constant suggested that the apparent volume of distribution of theophylline is increased in the presence of erythromycin. It is concluded that patients maintained on theophylline derivatives should be closely monitored when erythromycin is coadministered.     

The effects of atropine on pharmacokinetics of theophylline in rabbits.

The effects of atropine on serum concentrations and pharmacokinetics of theophylline were studied in six rabbits (2.07 +/- 0.11 kg). Theophylline serum concentration was determined by ultraviolet spectrophotometry. After i.v. administration of aminophylline 12.5 mg/kg, i.m. atropine 1 mg/kg decreased significantly the maximal serum concentration of theophylline from 23.6 +/- 1.1 to 19.6 +/- 1.1 mg/l, and increased that of theophylline at the time of 6 and 8 hours after injection. After i.v. aminophylline administration without or with atropine, the pharmacokinetic parameters of theophylline calculated using a one compartment open model were: K (elimination rate constant) = 0.23 +/- 0.03, 0.19 +/- 0.02/h; t1/2 (half life) = 3.04 +/- 0.40, 3.66 +/- 0.40 h; Cl (clearance) = 0.26 +/- 0.04, 0.23 +/- 0.03 l/kg/h, respectively (P less than 0.01). But there was no significant variation in modification of volume of distribution (Vd). The results suggested that there is a significant drug interaction between atropine and theophylline.     

Dose dependency for absorption and elimination rates of theophylline. Implications for studies of bioavailability

Dose dependency for absorption and elimination rates of theophylline were examined by administering 2-mg/kg and 6-mg/kg doses of a theophylline solution to 8 adult volunteers. The area under the concentration-time curve extrapolated to infinity after the lower dose was 84% of that calculated after the higher dose. This is associated with a decrease in the slope of the terminal portion of the elimination curve to varying degrees after the higher dose in all 8 patients (p less than 0.001). A significantly smaller fraction of the higher dose was absorbed at 15 minutes (0.46 vs. 0.77, p less than 0.002), but the differences were trivial by 30 to 45 minutes. Dose dependency for elimination may cause changes in a steady-state serum concentration during multiple dosing that is disproportionately larger than changes in dosage. In addition, the slower elimination at higher serum concentrations may confound the assessment of bioavailability of slow-release formulations when the doses used result in a substantial disparity in the range of serum concentrations attained for the slow-release formulation and the reference. The use of unequal doses adjusted to provide similar peak serum concentrations appears to minimize this potential error.     

Pharmacokinetics of theophylline in hyperthyroid and hypothyroid patients with chronic obstructive pulmonary disease

Summary The pharmacokinetics of theophylline was investigated in five hyperthyroid, five hypothyroid, and five euthyroid patients, all with chronic obstructive pulmonary disease. Wide individual variability was found in theophylline kinetics, but the rate of elimination of theophylline was significantly higher in hyperthyroid, and lower in hypothyroid patients than in the euthyroid patients (k_el=0.155, 0.060 and 0.107 h^–1, respectively). The values for clearance and volume of distribution were not consistently changed compared with those in the euthyroid group, although all the parameters except AUC were significantly different in hyperthyroid and hypothyroid patients. There was a positive correlation between both thyroxine and triiodothyronine serum concentrations and total body clearance of theophylline (r=0.795 and r=0.791, respectively). It is concluded that in spite of the wide interindividual variability and the relatively small differences in the pharmacokinetics of theophylline in thyroid dysfunction compared with the euthyroid status, these differences have to be considered in certain clinical situations, as they may require changes in the therapeutic regimen for administration of theophylline in hyperthyroid or hypothyroid patients.     

Pharmacokinetics of once-daily theophylline dose following the morning versus evening administration

The pharmacokinetics of theophylline (Uniphyllin) in blood and saliva was compared after morning and evening administration of a once-daily dose in a randomized cross-over study. Ten bronchial asthma patients received multiple doses of 800 mg theophylline at 8 a.m. and 8 p.m. under controlled food conditions. The precision of the serum concentration prediction from salivary measurements in individual patients was sufficient to obtain identical pharmacokinetic parameters and parallel concentration-time curves. There were no significant differences in the values of mean residence time and area under the concentration-time curves after morning and evening dosing, either in the kinetics of elimination and in the volume of distribution. The fluctuation of concentrations during the dosing intervals was 100% after morning doses and 80% after evening doses. No consistent interference with food was found. Circadian variation in the kinetics of drug disposition after once-daily theophylline administration did not occur. In order to achieve higher therapeutical levels at night and in the morning, the evening dosing seems to be preferable.     

Pharmacokinetics and relative bioavailability of oral theophylline capsules

The oral bioavailability of liquid-filled theophylline capsules relative to a nonalcoholic aminophylline solution was determined in normal volunteers. In addition, theophylline absorption and elimination kinetics were reexamined. There were no statistically significant differences between the bioavailability of capsules and liquid as measured by the area under the curve (AUC) from time 0 leads to infinity (p greater than 0.05). The bioavailability parameters of Cmax, tmax, and AUC were determined from actual serum theophylline concentration-time data and from a nonlinear least-squares fit of the serum concentration-time data. Theophylline absorption from the capsules was noticeably faster than from the liquid in most subjects, although the differences in absorption rates were not significantly different (p greater than 0.05). The determined apparent volume of distribution, elimination half-life, and plasma clearance of theophylline were similar to values reported by other investigators. Marked inter- and intraindividual variations in the elimination half-life were noted.     

Comparative Pharmacokinetics of Theophylline in Rabbits and in Humans with Hyperlipidemia

The study was carried out on male rabbits divided into two groups: a control and an experimental one, fed on a high-fat diet. Humans were also ascribed into two groups: control and those affected with primary, mixed form of hyperlipidemia. The animals and humans were given theophylline intravenously as a single dose. Blood was sampled after 5, 10, 15, 30 and 45 min and 1, 2, 4, 6, 8, 12 and 24 h following theophylline administration. FPIA method was used to determine blood serum concentrations of theophylline. Considerable alterations of theophylline pharmacokinetics in humans suffering from mixed form of hyperlipidemia were observed. Marked decrease in area under the concentration–time curve (AUC), diminished volume of distribution, increased total body clearance, and shortened elimination half-life were observed. On the contrary, in rabbits with alimentary induced lipid metabolism disturbancest_1/2of theophylline was practically unchanged and AUC only slightly increased. In conclusion: (1) hyperlipidemia affects the pharmacokinetics of theophylline in human beings, (2) rabbit model with dietetary induced lipid metabolic disturbances is not a suitable subject for estimation of pharmacokinetics of xanthine derivatives.     

Time-dependent absorption of theophylline in man

Sixteen healthy volunteers were given either oral or intravenous doses of aminophylline (125 mg) at 9:00 A.M. and 9:00 P.M. under controlled food conditions. Measured at regular time intervals by homogeneous enzyme immunoassay, the plasma theophylline concentrations 1.5 and 2 hours after oral aminophylline were significantly higher in the morning than in the evening (P less than 0.05). Also, the mean peak plasma concentration was significantly higher (P less than 0.05) and the time to peak concentration was faster (P = 0.02) after the morning dose. Neither the morning mean elimination half-life nor the morning mean area under the plasma concentration-time curve differed significantly from those after the evening dose. After intravenous aminophylline, no significant differences were found in the plasma theophylline concentrations and in the elimination half-life between morning and evening. Therefore, the small but statistically significant time-dependent differences in theophylline kinetics must be due to changes in absorption from the gastrointestinal tract and not to changes in distribution or elimination of the drug.     

Bioavailability studies of theophylline ethylcellulose microcapsules prepared by using ethylene-vinyl acetate copolymer as a coacervation-inducing agent

The bioavailability of theophylline microcapsules prepared by using ethylene-vinyl acetate (EVA) copolymer as a coacervation-inducing agent was studied in rats. The dissolution rate of the microcapsules was determined by the rotating-basket and rotating-bottle methods. The higher the concentration of EVA copolymer used, the more sustained was the release of theophylline from the microcapsules. The mean maximum serum levels (Cmax) and time to maximum serum levels (tmax) were not significantly different for theophylline microcapsules prepared by a lower concentration of EVA copolymer (0 and 0.83%, respectively), compared with those for theophylline powder; whereas a significant difference was found when the higher concentration of EVA copolymer was used (greater than 1.7%). With regards to the area-under-the-curve (AUC) value, there was no significant difference between the theophylline powder and theophylline microcapsules. The elimination kinetics and the corresponding half-life (t1/2) were significantly different when the concentration of EVA copolymer was greater than 3.3%. From the above results, it is evident that theophylline microcapsules prepared by using 3.3 and 5.0% EVA copolymer as the coacervation-inducing agent may act as sustained-release dosage forms. The correlation between the dissolution rate in vitro and the bioavailability in rats for theophylline microcapsules was investigated. The mean Cmax and tmax correlated well with the time taken to release 75% of the drug in vitro (t 75%); however, the mean AUC showed no valid correlation with t 75%. This implies that the dissolution rate correlated better with the rate of absorption (Cmax, tmax) than with the extent of absorption (AUC).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of four different types of food on the bioavailability of cefaclor.

This randomized, open-label, balanced, five-treatment, five-period, five-sequence, single-dose and crossover pharmacokinetic study assessed the effect of different types of food on the bioavailability of cefaclor in 18 healthy male volunteers. A single dose of cefaclor, 250-mg capsule was administered at five occasions: after overnight fasting, after two vegetarian (high-fat and low-fat) diets and two non-vegetarian (high-fat and low-fat) diets. Serial blood samples were collected upto 8 h post dose. Serum cefaclor concentrations were determined by a validated HPLC method. AUC values were not significantly affected by food intake, but the T(max) was prolonged and C(max) was decreased, depending on the type of meal. The non-vegetarian diets affected the rate of absorption of cefaclor more than the vegetarian diets. The least decrease in C(max) was produced by low-fat vegetarian diet, while the maximum decrease was produced by high-fat non-vegetarian diet. The results of this study indicate that while the rate of absorption of cefaclor is significantly decreased, the extent of absorption and the rate of elimination are not significantly decreased in the presence of food. As compared to high-fat non-vegetarian diet, the time above MIC50 concentration was significantly increased by low-fat vegetarian diet. The implications of these findings for the large vegetarian Indian population are considerable.     

Theophylline. A "state of the art" review

Theophylline is a bronchodilator and respiratory stimulant that is effective in the treatment of acute and chronic asthma, Cheyne-Stokes respirations, and apnea/bradycardia episodes in newborns. It is also used as an adjunct in the treatment of congestive heart failure and acute pulmonary edema, but it has no established efficacy in patients with chronic irreversible airways obstruction. Benefits and risks from theophylline relate directly to serum concentration, which is a function of both dose and elimination characteristics of the drug in an individual patient. When used to treat acute symptoms, an initial loading dose based on a mean volume of distribution is required to rapidly obtain maximum bronchodilator effect. Because of large interpatient differences in elimination, constant intravenous infusion rates for continued therapy must be guided by monitoring serum theophylline concentration at intervals until a steady-state serum concentration is reached within the 10-20 micrograms/ml therapeutic range. Intravenous, oral or rectal solutions and plain uncoated tablets are appropriate for acute therapy, while reliably absorbed slow-release formulations offer therapeutic advantages for the management of chronic asthma, particularly in patients with rapid elimination. Dosage for long-term therapy is determined by starting with low doses that allow virtually complete acceptance of the medication followed by gradual increases, if tolerated, at three day intervals until mean age-specific doses are reached. Subsequent adjustment in dosage regimens are then based upon serum concentration measurements. Most clinical laboratories now measure theophylline, and newer systems have been developed to provide emergency results within minutes at a reasonable cost. In cases of theophylline poisoning, the drug must be rapidly removed to prevent life-threatening toxicity. When serum concentrations are in excess of 60 micrograms/ml charcoal hemoperfusion dialysis may be indicated, even in the absence of obvious signs of toxicity.     

氧氟沙星对健康人茶碱药动学的影响

本文应用均相酶免疫法,测定了六名健康志愿者po氨茶碱及连续多次po氧氟沙星后po氨茶碱的血清浓度,以PKBP--N1程序包按一室模型对数据进行处理并对结果进行统计分析,结果:氧氟沙星对茶碱的消除速率常数及清除率未见影响(P>0.05),但对分布容积有显著增加(p<0.05)。     

The population pharmacokinetics of theophylline in neonates and young infants

The population pharmacokinetics of theophylline were evaluated using 391 theophylline serum concentration measurements from 108 neonates and young infants (postnatal age 0-26 weeks), who received theophylline for the treatment of neonatal apnea. A one-compartment pharmacokinetic model with first-order elimination was used, with intravenous aminophylline and oral theophylline administration modeled as zero-order infusions. The effect of a variety of developmental and demographic factors on clearance (CL) and volume (V) were investigated. Hypothesis testing to evaluate potentially significant factors produced a final model in which clearance was based on weight (kg) raised to an exponential power and postnatal age (weeks), with CL (ml/hr) = 17.5 (weight)1.28 + 1.17 (postnatal age). Clearance was reduced by 12% for patients receiving parenteral nutrition. Volume of distribution in this population was adequately described using only weight, with V (L) = 0.858 L/kg. Bioavailability of orally administered drug was not significantly less than unity. Interindividual variability in clearance was modest, with a coefficient of variation for clearance of 16%. An estimate of interindividual variability in volume could not be obtained. As a measure of residual variability in theophylline serum concentrations, the coefficients of variation for theophylline serum concentrations of 5.0, 10.0, and 13.0 mg/L were found to be approximately, 25, 12, and 9%, respectively. The identification of influential patient factors and the quantification of their influence on theophylline disposition allow for a priori estimates of theophylline pharmacokinetic parameters in these patients.     

Comparative pharmacokinetic analysis of theophylline in serum and saliva

The kinetics of theophylline disposition in serum and saliva was evaluated after single and multiple circadian administration of a sustained-release theophylline formulation (Euphyllin CR) to 20 asthmatic children. Salivary concentrations were proportional to serum drug levels, with the significant correlation of r = 0.92. The kinetics of theophylline absorption and elimination and the mean residence time were identical in both saliva and serum estimations. In steady-state conditions after multiple drug administration, the area under the concentration-time curve and the magnitude of peak levels in saliva were reduced proportionally with decreased serum theophylline concentrations. The significantly higher volume of theophylline distribution in saliva confirmed that salivary concentrations represent the free, pharmacologically active fraction in plasma. The determination of theophylline salivary levels could therefore be of clinical importance. The values of the saliva/serum ratio determined in the elimination phase of concentration-time curves for individual patients were constant and stable over the treatment period of three weeks. Saliva appears to be a convenient and noninvasive alternative to blood for the assessment of the variable pharmacokinetic parameters of theophylline and for around-the-clock monitoring of individual dosage regimens, especially in paediatric patients.     

Interaction between chloroquine sulphate and aqueous extract of Azadirachta indica A. Juss (Meliaceae) in rabbits

This study was carried out to investigate the effect of concurrent oral administration of aqueous leaf extract of Azadirachta indica (Meliaceae) on the pharmacokinetic properties of chloroquine sulphate in experimental rabbits. The results indicated that concurrent administration of both agents resulted in a significant decrease in serum concentration, slower absorption and elimination as well as longer half-life of chloroquine sulphate. The highest relative decrease of 78.0% was recorded 4 hours after concurrent administration, while the smallest decrease (64.6%) occurred 24 hours after concurrent administration. Significant reductions were also noted in some pharmacokinetic parameters of chloroquine and included the area under the curve (71.9%), maximum serum concentration (69.8%), absorption rate constant (37.3%), elimination rate constant (53.9%), clearance rate (76.5%) and volume of distribution (47.2%). However, there was a pronounced increase in the half-life of the drug (125.7%).     

Pharmacokinetics of cycloserine under fasting conditions and with high-fat meal, orange juice, and antacids.

STUDY OBJECTIVES: To determine the effect of a high-fat meal, orange juice, and antacids on absorption of a single oral dose of cycloserine and to estimate its population pharmacokinetic parameters. DESIGN: Randomized, four-period, crossover study. SETTING: Clinical research center. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Subjects received single doses of cycloserine 500 mg after a 12-hour fast (reference), with a high-fat meal, with orange juice, and with antacids. They also received clofazimine 200 mg, ethionamide 500 mg, and p-aminosalicylic acid granules 6000 mg. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected for 48 hours and assayed by validated high-performance capillary electrophoresis assay. Concentration-time data were analyzed with noncompartmental, one-compartment, and population methods. The maximum concentration (Cmax) of cycloserine was decreased (p=0.02) by the high-fat meal. No other statistically significant differences were observed for Cmax and area under the curve from time zero to infinity across the four treatments. The high-fat meal significantly (p<0.0001) delayed time to maximum concentration by 4.7 times compared with that of the reference (1.1 hr). CONCLUSION: The pharmacokinetics of cycloserine were minimally affected by orange juice and antacids, whereas the high-fat meal delayed absorption. Administering cycloserine without a high-fat meal avoids potential alterations in the pattern of absorption.     

The effect of four different types of diet on the bioavailability of loracarbef.

This randomized open-label single-dose crossover pharmacokinetic study was carried out to assess the effect of different diets on the bioavailability of loracarbef in 24 healthy male volunteers. A single dose of loracarbef in 200-mg tablet form was administered at 5 different times: after overnight fasting, after two vegetarian (high-fat and low-fat) diets, and following two non-vegetarian (high-fat and low-fat) diets. Serial blood samples were collected up to 10 h post-dose. Serum loracarbef concentrations were determined by a validated high performance liquid chromatographic (HPLC) method. Area under curve (AUC) values were significantly affected only by non-vegetarian diets; however the time to reach maximum serum concentration (Tmax) was prolonged and the maximum serum concentration (Cmax was decreased by all types of meals. The non-vegetarian diets affected the rate of absorption of loracarbef more than the vegetarian diets. The lowest decrease in Cmax was produced by the high-fat vegetarian diet, while the maximum was produced by the low-fat non-vegetarian diet. The results of this study indicate that while the rate of loracarbef absorption is significantly decreased by all diets, the extent of absorption is only reduced significantly by the non-vegetarian diets. The rate of elimination (k(el)) was not found to be significantly decreased by any of the diets. As compared to the high-fat non-vegetarian diet, the time beyond minimum inhibitory concentration (MIC90) concentration was significantly increased by the high-fat vegetarian diet. The implications of these findings for the large Indian vegetarian population are considerable.     

Evaluation of the effect of variability in the volume of distribution of theophylline on the predictability of the iterative and the Chiou methods using computer simulations

The effect of variations in the volume of distribution on the precision of the ability of two methods--the Chiou and the iterative--to predict the total body clearance (TBC) of theophylline was evaluated utilizing computer simulations. Pharmacokinetic data [volume of distributions (V), elimination constants (k)] measured in a group of 55 adult bronchitic patients were utilized to conduct the simulations. An average V of 0.45 L/kg was utilized to calculate TBC with the Chiou and the iterative methods. Separate simulations were conducted utilizing initial (C1) serum concentrations of 2 and 10 micrograms/ml. At the C1 = 2 micrograms/ml condition, the iterative method was statistically significantly more precise (mean squared prediction error, 379.5 vs. 508.5). There were no differences when the initial serum concentration was 10 micrograms/ml under the simulated conditions. At the lower initial condition (C1 = 2) the mean prediction error was 62.3 and 54.9% for the Chiou and the iterative methods, respectively, and it ranged from 0 to 477%. It is recommended that caution be utilized when theophylline doses are individualized using these methods.     

Dose-dependency in the exsorption of theophylline and the intestinal dialysis of theophylline by oral activated charcoal in rats

The elimination half-life of theophylline in serum after intravenous (i.v.) administration of aminophylline increased with increase in dose. Exsorption of theophylline from blood to the gastrointestinal tract was investigated after i.v. administration of aminophylline (10-50 mg kg-1) to rats by the in-situ single-pass perfusion technique. The exsorption rate of theophylline into the intestinal lumen also increased with increase in dose. When the dose of aminophylline was increased five-fold from 10 to 50 mg kg-1, the amount of theophylline exsorbed in 120 min was proportionally increased from 450 to 2300 micrograms. The average extent of theophylline exsorbed into the intestinal lumen was 12-15% after doses from 10-50 mg kg-1, while the extent of the drug excreted into the bile varied from 0.17-0.30% after doses from 10-50 mg kg-1. However, intestinal and biliary clearance of theophylline did not change significantly in the range 10 to 50 mg kg-1. Oral administration of multiple doses of activated charcoal reduced the serum theophylline levels after i.v. administration of aminophylline (50 mg kg-1) to rats. The serum half-life and the area under the serum concentration-time curve of theophylline were decreased to 52 and 50% by the charcoal treatment, respectively, while the total body clearance of the drug was increased to 188% compared with the corresponding control experiments. The volume of distribution was not significantly different between treated and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment.

The disposition of a single 20-mg oral dose of pravastatin was assessed in subjects with various degrees of renal function. Sixteen subjects (13 males, 3 females) with creatinine clearance values ranging from 15 to 112 mL/min/1.73 m2 completed the study. Area under the serum concentration-time curve, maximum serum concentration, time to maximum serum concentration, terminal serum elimination half-life, apparent clearance, and apparent volume of distribution for pravastatin were not affected by renal impairment, whereas the renal clearance of pravastatin decreased as creatinine clearance decreased (r2 = 0.697, P less than .001). The area under the serum concentration-time curve and time to maximum serum concentration of SQ 31,945 (a hepatic metabolite) increased in patients with renal impairment, whereas the terminal elimination rate constant and renal clearance of SQ 31,945 significantly decreased as a function of creatinine clearance. The renal clearance of another metabolite (SQ 31,906) also significantly declined with decreasing renal function. This single-dose study demonstrates that pravastatin pharmacokinetics were not affected in patients with renal impairment, probably because of its dual route of elimination.