Pharmacokinetics of a sustained-release theophylline formulation.

1 Plasma theophylline concentrations following administration of sustained-release (SR) theophylline tablets were determined in ten healthy volunteers using a dose of 190 mg or 380 mg 12 hourly. 2 The plasma theophylline levels during the first 12 h period confirmed the sustained-release formulation characteristics, with the plasma drug concentrations reaching a plateau for the last 6 hours. 3 During the fifth 12 h dosing period the mean maximum and minimum plasma theophylline concentrations were 7.25 and 4.30 microgram/ml after 190 mg SR theophylline 12 hourly (n = 6) and 12.96 and 7.36 microgram/ml after 380 mg 12 hourly (n = 5), although there was marked between-subject variation in plasma theophylline concentrations. 4 One subject withdrew from the study due to side effects, which were more common when the higher dose of SR theophylline was given.     

三种茶碱缓释剂的药动学和生物利用度研究

本实验应用均相酶免疫法和PKBP—N_1程序包对六名健康志愿者分别口服三种茶碱缓释剂后的药动学参数和相对生物利用度进行了探讨,结果表明:三者的生物利用度、吸收速率常数和波动百分率均无显著差异(P>0.05)。     

8例中国病人茶碱代谢物的药物动力学

目的：研究病人常规剂量茶碱治疗后代谢物的动力学。方法：病人静滴茶碱（６．６μｍｏｌ·ｋｇ＾－１）。ＨＰＬＣ法测定给药前后２４ｈ茶碱及其代谢物：１，３－二甲基尿酸（ＤＭＵＡ），３－甲基黄嘌呤（３－ＭＸ），１－甲基尿酸（ＭＵＡ），中间代谢产物１－甲基黄嘌呤（１－ＭＸ）的浓度。结果：ＤＭＵＡ是代谢物中浓度最高的。３－ＭＸ的清除速率最低。１－ＭＸ很快转化成ＭＵＡ，体内浓度很低，但是，翌晨，１－ＭＸ又回升到     

Pharmacokinetics of theophylline in protein-calorie malnutrition

The influence of protein-calorie malnutrition (PCM) on the disposition of theophylline was investigated in male Sprague-Dawley rats fed for four weeks on a 23 per cent (control) or 5 per cent (low) protein diet ad lib. Dietary protein deficiency led to a decrease in body weight gain, plasma proteins, albumin, microsomal proteins, and cytochrome P-450. After intravenous administration of aminophylline equivalent to 10 mg kg-1 theophylline, the average mean residence time (MRT) was 58 per cent higher in the protein-deficient rats, while the total plasma clearance (Cl) per kilogram of body weight and elimination rate constant (k) were decreased by 39 per cent and 45 per cent, respectively, when compared to rats on a normal protein diet. No significant difference was found in the two groups of animals with respect to the apparent steady-state volume of distribution (Vss). The present results suggest that the mechanism responsible for the observed pharmacokinetic changes in the protein-deficient rats is related to the reduced amount and/or activity of the hepatic mixed function oxidases.     

Pharmacokinetics of theophylline and enprofylline in patients requiring a high or low dose of theophylline

Summary In patients requiring a high or low dose of theophylline the pharmacokinetics of theophylline and enprofylline were studied. The low-dose group took an average daily dose of 8.91 mg/kg body wt. and the high-dose group 24.75 mg/kg body wt. The average half-life of theophylline in the former was 7.11 h and in the latter 4.72 h. The average clearances (CL) of theophylline were 2.83 and 4.58 l/h, respectively. The daily oral intake of theophylline was negatively correlated with the theophylline t_1/2 (r=–0.63). While the t_1/2 of enprofylline was similar in the two groups, CL and volume of distribution (V_c) were slightly (about 30%) but significantly higher in patients requiring a high dose of theophylline. CL of enprofylline did not correlate with CL of theophylline, nor was the V_c of the two drugs correlated. Interindividual variability in t_1/2 and CL was considerably lower for enprofylline than for theophylline.     

Pharmacokinetics and biologic availability of a new theophylline sustained-release preparation

Pharmacokinetics and bioavailability of a new anhydrous sustained release theophylline preparation (GTR-80 300 mg, Theospirex) were compared to those of an orally administered marketed solution containing theophylline-ethylenediamine and to a sustained release preparation containing theophylline-ethylene-diamine (control preparation). Eight healthy volunteers received in a cross-over design GTR-80 (300 mg) and the control preparation (350 mg) at single doses - nine volunteers received the solution in a quantity corresponding to 200 mg anhydrous theophylline. During the observation period 0-24 h the relative bioavailability of GTR-80 (calculated on the basis of equivalent doses) was 135% versus control preparation and 80% versus solution. During the observation period 0-36 h, the comparison of the dose-adjusted areas under the serum level-time curves of GTR-80 showed 116% versus control preparation and 91.5% versus solution. Statistical evaluation revealed significant differences in the observation period 0-24 h. Extrapolation of the solution's serum values indicated a shift towards the non-significant range for the observation period 0-36 h. The protracted action of GTR-80 300 mg could be demonstrated by the significantly longer period elapsing before reaching serum peaks compared to that after dosing of the fast absorbing solution. The lower interindividual deviations with respect to the parameters of Cmax and AUC after administration of GTR-80 as against the control preparation should be of interest in therapeutical use.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of theophylline in ten elderly patients

The two-compartment pharmacokinetics of theophylline in ten hospitalized elderly patients with apparently normal renal, hepatic and cardiopulmonary functions was investigated after intravenous administration of the drug. Nine patients suffered from slight hemiparesis and one from Parkinson's disease. Biological theophylline half-lives of 5.4--9.0 hours and plasma clearence values of 28--42 ml kg-1hr-1 were found. The apparent volumes of distribution during the beta-phase, Vdbeta, were 0.33--0.43 1 kg-1. It is concluded that a therapeutic concentration of about 10 microgram theophylline per ml serum could be established in the investigated group of elderly patients following an intravenous initial loading dose of 3.7 mg theophylline per kg followed by a continuous infusion of 0.35 mg per kg body weight per hour. In the therapeutic use of theophylline monitoring of the serum theophylline concentration is generally advised because of the elsewhere reported variability in the biological half-life of the compound.     

Pharmacokinetics of theophylline in Guinea pig tears

It is well recognized that the theophylline (TP) concentration in human tears correlates well with the free TP concentration in human plasma. However this correlation was found only in a very narrow range of concentrations of TP, and pharmacokinetic analysis of TP in tears has not been carried out for a wide range of concentrations of TP. The aims of this investigation were to develop a simple kinetic model for TP in guinea pig plasma (total [Cf+b] and free [Cf]), cerebrospinal fluid (CSF) [C](CSF) and tears [C](T), and to examine whether [Cf], [Cf+b] and [C](CSF) can be predicted from [C](T) using the resulting kinetic parameters. [Cf+b], [Cf], [C](CSF) and [C](T) were determined by GC/EI-SIM following bolus i.v. injection of TP in doses of 10, 50 and 100 mg/kg into guinea pigs. The wide range of concentrations of [Cf+b] could be quantitatively described by a two-compartment model with non-linear elimination kinetics and individual volume distribution of TP at each dose. [C](T) and [C](CSF) were analyzed using passive diffusion models with and without the pH-partition theory, respectively. The value of [Cf] could be predicted from the value of [C](T). Thus, the measurement of [C](T) which can be collected non-invasively would be a useful method for the therapeutic drug monitoring of TP.     

Pharmacokinetics of theophylline in infants with bronchiolitis

Summary Single-dose investigations in healthy subjects have demonstrated substantial impairment of renal and extrarenal clearance of digoxin during coadministration of verapamil. A longitudinal study has been performed to assess the changes in digoxin disposition during long-term verapamil therapy. After one week of verapamil 240 mg/d mean plasma digoxin had risen from 0.21±0.01 ng/ml (SE) to 0.34±0.01 ng/ml (p<0.01), and renal digoxin clearance had fallen from 197.57±17.37 ml/min to 128.20±10.33 ml/min (p<0.001). These changes gradually subsided, and after six weeks, renal digoxin clearance had normalized and plasma digoxin had declined to 0.27±0.02 ng/ml (NS). The 24-h urinary recovery of digoxin increased from 46.46±3.23% before to 69.78±3.69% (p<0.001) after six weeks of verapamil co-administration, and this elevation persisted throughout the study. The verapamil-induced suppression of renal digoxin elimination disappears over a few weeks of drug exposure, whereas the inhibition of the extrarenal clearance of digoxin seems to persist.     

Pharmacokinetics and pharmacodynamics of slow-release theophylline during treatment with nimesulide.

The pharmacodynamic and pharmacokinetic interactions were studied between nimesulide, a recently introduced non-steroidal anti-inflammatory drug, and theophylline, another highly protein-bound drug, in patients who were receiving slow-release theophylline for a chronic airflow-obstruction and who also needed anti-inflammatory treatment. A good tolerability was demonstrated of the two drugs association and there was an absence of pharmacodynamic interaction, as shown by lung function parameters, assayed before and after the coinciding nimesulide association. The pharmacokinetics of nimesulide and 4-hydroxy-nimesulide (its active metabolite) were not modified, in agreement with data shown by other authors. On the contrary, there was a slight alteration of theophylline pharmacokinetics, yet neither clinically nor biologically significant, probably due to an enzymatic induction.     

Pharmacokinetics of buspirone extended-release tablets: a single-dose study.

The objective of this study is to evaluate the absorption of buspirone and its biotransformation to 1-(2-pyrimidinyl) piperazine (1-PP) from two different extended-release (ER) formulations of buspirone HCl tablets (12-hour and 24-hour in vitro release) and from a commercially available immediate-release (IR) tablet. A single dose of the 30 mg ER tablets was compared with two doses of the 15 mg IR tablet administered 12 hours apart. Eighteen healthy male subjects participated in this randomized, open-label, three-treatment crossover study. Blood samples were obtained at 22 time points from predose (0 hour) until 36 hours postdose, and plasma concentration of buspirone and 1-PP was determined by LC/tandem mass spectrometry method. The pharmacokinetic parameters AUC0-t, AUC0-infinity, Cmax, tmax, Ke, and t1/2 were calculated and statistically analyzed. The results indicated extended release of buspirone from the two test products in vivo with a 70% to 90% greater bioavailability in comparison with the IR formulation. The bioavailability of 1-PP from ER formulations appears to be equal to that from the IR formulation. Both buspirone ER tablets successfully delivered bioavailable buspirone with a reduction in peak drug and metabolite plasma levels, prolonged buspirone plasma concentrations, and decreased ratio of 1-PP to buspirone concentration with less intersubject variation when evaluated as a single-dose study in healthy human subjects.     

Pharmacokinetics of theophylline and its metabolites in rabbits

The pharmacokinetics of theophylline (1,3-DMX) and its metabolites were investigated in detail in four male rabbits after bolus intravenous injection (12 mg/kg) of the compound. Theophylline was measured in blood and urine, and its metabolites were determined only in urine. Apparent first-order rate constants for the metabolic processes involved in the formation of 1,3-DMX metabolites and their excretion in urine were calculated. An appropriate 13-compartment model was formulated to describe the disposition of 1,3-DMX and its metabolites.     

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.     

Pharmacokinetics of sustained release theophylline in low and high multidose regimens.

1 The in vitro characteristics (dissolution rate) of a sustained release theophylline preparation (Theo-Dur were first measured in acid medium (pH = 1) for 2 h and after that in a phosphate buffer (pH = 6.8) for 6 h. 2 The tablets released more than 95% of the active ingredient within 5 h at a rate of approximately 11% of the dose per hour at pH = 1 and about 18% at pH = 6.8. 3 Dose dependency of the pharmacokinetics of theophylline was tested in seven healthy volunteers by giving them either 300 mg Theo-Dur or 900 mg Theo-Dur in two doses a day for 5 days in a cross over design. After the last tablet on day 6 the fall-off curve was followed in order to calculate the pharmacokinetic parameters. 4 Theophylline (300 mg) resulted on day 6 in a mean serum concentration of 4.4 +/- 0.8 microgram ml-1. The dose of 900 mg resulted in a proportional increase in the serum concentration. The result was 13.3 +/- 2.2 micrograms ml-1. 5 The T1/2 (300 mg) was 9.3 +/- 1.4 h and the T1/2 (900 mg) was 8.5 +/- 2.0 h. These values do not significantly differ (0.10 less than P less than 0.20). 6 It was concluded that theophylline exhibits the rules of linear pharmacokinetics when serum concentrations are in the therapeutic range.     

Pharmacokinetics of theophylline in patients following short-term intravenous infusion

Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin^® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, V_d=0.451 (0.258–0.789) l/kg ideal body weight, and t_1/2(el)=7.1 (2.6–19.1) h.     

Pharmacokinetics of theophylline before and after nephrectomy in dogs

The role of the kidneys in the elimination of theophylline was directly assessed using nephrectomized dogs. Data was analyzed by two different pharmacokinetic approaches. Analysis indicated that a given dosage regimen produced significantly different serum concentrations before and after nephrectomy. Model independent pharmacokinetic analysis failed to show a significant difference in parameters. A model dependent approach, using a nonlinear regression analysis employing a linear two-compartment model, demonstrated that the differences observed could be accounted for by a change in the first order elimination kinetics.     

Pharmacokinetics of theophylline and its metabolites during acute renal failure. A case report.

After unsuccessful therapy with salbutamol syrup and inhaled terbutaline a 3-year-old boy with an acute exacerbation of asthma was treated with nebulised salbutamol (albuterol), intravenous aminophylline and hydrocortisone. His condition continued to deteriorate and he required artificial ventilation. Subsequently, he became anuric, with liver dysfunction, nonspecific encephalopathy and limb tremor. Peritoneal dialysis was started. Plasma theophylline concentrations were monitored and maintained in the therapeutic or subtherapeutic range. Despite this, he was hyper-reflexic with limb tremor. Excessively high plasma concentrations of the principal theophylline metabolite, 1,3-dimethyluric acid, were found [maximum 92 mg/L (470 mumol/L)], which cleared only with the return of normal renal function. Plasma concentration monitoring of drugs other than theophylline was not performed. After the patient recovered, a pharmacokinetic study demonstrated that normal methylxanthine metabolism was re-established. Pharmacokinetic analysis indicated that the undue accumulation of the metabolites was a result of an inability to clear these compounds. Thus, pharmacologically and toxicologically active metabolites of theophylline may accumulate in anuric patients on peritoneal dialysis, producing clinical symptoms of toxicity. However, in the present case the possible role of metabolites of other drugs cannot be definitely excluded.