Absorption of intra-bronchial diprophylline-methodology and preliminary results.

With the objective of measuring alveolo-capillary permeability, a diprophylline solution (molecular weight 254 D) was instilled as a bolus. Instillation was performed through distallized impacted fiber bronchoscope and 3 normal volunteers and 3 patients with pulmonary fibrosis were evaluated. Blood samples were collected at regular intervals with subsequent pharmacokinetic study, mainly aimed at determining absorption kinetics. This technique enabled us to distinguish the two groups of individuals which had different absorption rates. In controls, kinetics apparently followed a simple, one compartment model for absorption, which was slower and occurred to a lesser extent. Patients with a pulmonary fibrosis had a faster and higher degree of absorption, with a larger plasma Cmax. In the latter group two-compartment kinetics for absorption was found. We conclude that absorption kinetic parameters can disclose data on structural integrity of epithelia and possible lesions of the lung interstitium.

Pharmacokinetic characteristics of N7-substituted theophylline derivatives and their interaction with quinolone in rats.

Disposition of diprophylline (DPP) and proxyphylline (PXP) and the effect of enoxacin on their disposition were investigated in rats. Concentrations of the two drugs in plasma and urine were measured by HPLC. The pharmacokinetic parameters of the two drugs were estimated by model-independent methods. Although the chemical structures of the two drugs are very similar, remarkable differences in the disposition of the two drugs were observed. Total body clearance (CLT) of DPP was 1.77 L/h/kg, which was sevenfold greater than that of PXP (0.26 L/h/kg). Diprophylline was excreted in an almost completely unchanged form in the urine, but only 50% of PXP was excreted. However, no binding of either drug to proteins in rat plasma was observed. The DPP renal clearance (CLR) was 1.75 L/h/kg, approximately 13-fold the CLR for PXP (0.13 L/h/kg) and sevenfold the rat glomerular filtration rate. This study indicates that in rats, DPP is mainly excreted by active tubular secretion and that renal tubular reabsorption contributes to renal excretion of PXP with glomerular filtration. No significant changes in any pharmacokinetic parameters of the two drugs were observed when they were coadministered with enoxacin, compared with the drug administered alone, suggesting that enoxacin had no effect on the pharmacokinetics of either drug.

Non-extraction HPLC method for simultaneous measurement of dyphylline and doxofylline in serum.

A direct injection HPLC method for the simultaneous measurement of dyphylline and doxofylline in serum is reported. Chromatography is carried out with a "Pinkerton" internal surface reversed-phase column and phosphate buffer (0.1 mol/L, pH 6.8) as mobile phase. Absorbance at 275 nm is monitored. Only 10 microL of serum is required to detect less than 1 mg of each drug per liter in biological samples. The standard curve for the method is linear over the range 6-100 mg/L, and precision is acceptable for both drugs, with CVs of 2% and 1.5% for respective concentrations of 6.2 and 25 mg/L. None of the 76 drugs tested for interference affected the measurement of either drug. Four samples can be injected per hour. This method provides a fast, accurate way to monitor two interesting therapeutic agents used in chronic obstructive airway diseases.

Dyphylline prodrugs: plasma hydrolysis and dyphylline release in rabbits.

Ester hydrolysis of prodrugs of dyphylline [7-(2,3-dihydroxypropyl)theophylline] followed first-order kinetics in both human and rabbit plasma. Rate constants were estimated by linear regression analysis of initial conversion rates, determined at different initial prodrug concentrations. Release of dyphylline from different prodrugs was 1.3 to 13 times faster in rabbit plasma than human plasma. However, relative rates of drug release (lability order) followed the same patterns in rabbit and human plasma. Dyphylline concentrations in rabbit plasma were extended slightly following intravenous administration of dyphylline 2',3'-dipivaloate. Oral dosing of the prodrug in rabbits greatly sustained plasma dyphylline concentrations.

Microassay for the simultaneous determination of theophylline and dyphylline in serum by high-performance liquid chromatography.

An improved and simplified high-performance liquid chromatographic method is presented for the simultaneous determination of theophylline and dyphylline in serum. The internal standard, beta-hydroxyethyltheophylline (20 microliters of a 100 micrograms/ml solution) is added to 50 microliters of serum. Serum proteins are precipitated by the addition of 30 microliters of 40% trichloroacetic acid solution. The mobile phase consists of a sodium acetate buffer with 6% acetonitrile. Chromatogram run time is 6 min. The sensitivity limit for both compounds is 0.25 micrograms/ml. This method is interference-free from the major metabolites of theophylline and other drugs commonly coadministered with theophylline.

Protective effect of methylxanthines against carbachol-induced bronchoconstriction in normal subjects.

The bronchoprotective effect of bioequivalent doses of theophylline (TH; 234 mg) and a combination of TH, proxyphylline (PPH) and diprophylline (DPH) in the proportion 2:3:3 (Neo-Biphyllin, NB; 600 mg) against carbachol-induced bronchoconstriction was studied in 10 healthy non-smokers in a randomised controlled double-blind cross-over trial. The subjects were on a methylxanthine-free diet 4 days prior to and during each study day. Bronchial provocation tests were conducted in the morning and afternoon of the three separate study days--control and two medication days--using a standardised technique. On the control day, the dose of carbachol required to reduce the partial expiratory flow volume at 25% of vital capacity (V25p) by at least 25% was established. A significant protective effect was achieved with both TH (p less than 0.05) and NB (p less than 0.001) as measured by V25p. Bronchoprotection was achieved with low maintenance serum levels of TH.

Theophylline and dyphylline pharmacokinetics in the horse.

The pharmacokinetics of theophylline and dyphylline were determined after IV administration in horses. In a preliminary experiment, the usual human dosage (milligram per kilogram) of each drug was given to 1 horse. Results were used to calculate dosages for a cross-over study, using 6 horses for each drug. Theophylline plasma concentrations decreased triexponentially in 5 of 6 healthy horses after IV infusion of 10 mg of aminophylline/kg of body weight for 16 to 32 minutes. In the 6 horses, total body elimination rate constants were variable, and the half-life of theophylline was 9.7 to 19.3 hours. Clearance was 42.3 to 69.2 ml/hr/kg. The initial distribution phase was rapid (t1/2 approx 3.5 to 4 minutes); a 2nd distribution phase was slower (t1/2 approx 1.5 to 2 hours). Plasma concentrations of theophylline were in the assumed effective range (10 to 20 micrograms/ml) from 15 minutes until 40 minutes after time zero. The mean apparent volume of distribution was 1.02 L/kg. After bolus IV injection of dyphylline (20 mg/kg), pharmacokinetics were best described by a 2-compartment open model in 2 horses and by a 3-compartment open model in 4 horses. In the 6 horses, elimination half-life of dyphylline was 1.9 to 2.9 hours, and clearance was 200 to 320 ml/hr/kg. Plasma concentrations (approx 50 micrograms/ml) were observed at 10 minutes after injection without adverse effects. Concentrations greater than 10 micrograms/ml were observed from time zero to about 1.5 hours after injection. Theophylline induced significant increases in heart rate, but dyphylline did not affect heart rate significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability of dyphylline and dyphylline-guaifenesin tablets in humans.

A six-way-crossover bioavailability study was conducted with twelve healthy male volunteers to evaluate the relative bioavailability of three tablet formulations containing dyphylline and three tablet formulations containing dyphylline-guaifenesin. Each subject was administered two tablets of each product with greater than or equal to 3 d separating each dose. Blood samples were obtained just prior to each dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 10.0 h following each dose. An HPLC method was used to assay dyphylline in the serum. The mean tmax ranged from 0.6 to 1.0 h for the six products. The mean values for Cmax differed by 29%, and the AUC values differed by less than 8%. It was noted that the dyphylline-guaifenesin products exhibited a lower bioavailability than the products which only contained dyphylline. It was concluded that the three combination products were bioequivalent, as were the three dyphylline products.

[Comparative studies on the tolerance of bioequivalent doses of intravenous methylxanthine preparations in healthy subjects]. / Vergleichende Untersuchungen zur Verträglichkeit bioäquivalenter Dosen intravenöser Methylxanthin-Zubereitungen bei gesunden Probanden.

In a comparative tolerance study with two different intravenous methylxanthine preparations, a theophylline-ethylendiamine preparation (TE-reference preparation) was tested against a combination of theophylline, proxyphylline (7-(2-hydroxypropyl)-theophylline) and diprophylline (7-(2,3-dihydroxypropyl)-theophylline) (Neobiphyllin; TPD = test preparation) in 10 healthy volunteers by a single blind cross-over design. Both preparations were infused under continuous control of vital parameters (blood pressure, pulse, respiration frequency, heart rhythm) as infusions (1 ampoule with 800 mg TPD or 1 short-infusion with 480 mg of TE for 20 min, each) up to the individual tolerance limit or the pre-defined limit of 3 ampoules/short infusions, respectively. The maximum tolerated infusion time and the serum levels at which the first side-effects appeared, were compared. These maximum doses could be administered to 6 volunteers under TPD, but only to two under medication with the reference preparation. Side-effects under TPD occurred in 5, after infusion of the reference preparation in 9 volunteers. Serum levels of theophylline at the end of the infusion period reached (14.6 +/- 4.21 (TPD) and 23.01 +/- 6.02 mg/l (TE), respectively. The average infusion time for the test preparation was 54.8, for the reference preparation 46.2 min. The average serum theophylline levels of the 5 volunteers with side-effects under TPD reached--when these side-effects occurred --11.26 +/- 4.52 mg/l; the same volunteers showed after administration of TE levels of 14.94 +/- 7.49 mg/l. Our results showed an approx. additive effect of the side-effects together with an--according to literature--over-additive pharmacological effect of the single components of TPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous determination of diprophylline, proxyphylline and theophylline in serum by reversed-phase high-performance liquid chromatography.

A selective and reliable high-performance liquid chromatographic assay for the simultaneous determination of diprophylline, proxyphylline and theophylline is described. The method involves a single extraction procedure followed by separation on an ODS reversed-phase column using a ternary solvent system. The assay is sufficiently rapid and sensitive to be applied for pharmacokinetic studies as well as for routine monitoring of patient's serum after therapeutic doses of the combined preparation. The practicability and utility of the proposed method is demonstrated in a pharmacokinetic study on four healthy volunteers.

Theophylline, dyphylline, caffeine, acetaminophen, salicylate, acetylsalicylate, procainamide, and N-acetylprocainamide determined in serum with a single liquid-chromatographic assay.

We describe a single set of liquid-chromatographic conditions for assay of theophylline, dyphylline, caffeine, acetaminophen, salicylate, acetylsalicylate, procainamide, and N-acetylprocainamide in serum. The chromatographic system includes a Waters Associates mu-Bondapak C18 column and acetonitrile in 0.1 mol/L potassium phosphate buffer, pH 4.0 (9.75/90.25 by vol), as the mobile phase. Only 50 microL of serum is required, and drug concentrations as low as 0.5 mg/L can be detected. Absolute and relative analytical recoveries range from 95 to 101%. Day-to-day variation of the method is less than 6% for each drug. Linearity extends to 1 g/L for all drugs. Recycling of the mobile phase under pressure eliminates the need to prepare and de-gas solvents. The use of the single stationary and mobile phase provides a practical and economical approach to routine and urgent therapeutic drug monitoring.

[Pharmacokinetic and clinical effectiveness of rectally administered theophylline]. / Pharmakokinetik und klinische Wirksamkeit rektal verabreichter Theophylline.

The bronchodilatory effect of Neo-Biphyllin Mikroklysma (400 mg Theophylline [T], 600 mg Diprophylline [D], 600 mg Proxyphylline [P], corresponding to 5.2 mg/kg bodyweight of T, and 7.8 mg/kg of D and P, respectively) was studied on 5 consecutive days with one daily rectal application in a double-blind crossover design in 8 patients with chronic obstructive lung disease. Serum levels following rectal application are lower than after oral administration. On the 5th day they are only slightly higher than on the 1st day. The mean serum levels (microgram/ml) achieved after 2 h are 6.1 for T, 1.0 for D and 7.7 for P, after 8 h 3.5 for T, 0.9 for D and 4.8 for P. The pulmonary function parameters (FEV1, VC, RV, TLC and Raw) show an improvement, however, in comparison with placebo the results are statistically not significant. A correlation between the serum levels and the functional improvement cannot be established, even after taking into consideration the equipotency on a weight-for-weight basis according to the in vitro effect of the three compounds on the isolated guinea pig trachea [Boardman, 1980]. No side effects or local intolerance were reported. The use of the combination enema is particularly suitable for children or self-application by adults. Yet according to our findings larger doses or more frequent applications are required.

Dyphylline elimination kinetics in lactating women: blood to milk transfer.

A population of 20 normal lactating females between the ages of 20 and 35 years was treated with a single 5 mg/kg intragluteal dose of dyphylline, 7-(2,3-dihydroxypropyl)theophylline. The distribution of the drug between blood and milk and its pharmacokinetics of elimination were determined. The apparent volume of distribution (Vd) of dyphylline was found to be 0.505 +/- 0.162 l./kg, the elimination rate constant (Kel) was 0.228 +/- 0.055 hr-1, the biological half-life (t1/2) was 3.21 +/- 0.76 hr, and the total body clearance (CI) was 0.109 +/- 0.036 l./kg/hr. The ratio described by dyphylline distribution between milk and serum (M/S) was 2.08 +/- 0.52. The elimination rate from milk was equivalent to that from blood.

Pharmacokinetics of dyphylline elimination by uremic patients.

The elimination kinetics of dyphylline were investigated in four uremic patients receiving chronic hemodialysis treatment. Dyphylline (1000 mg) was administered to each patient orally 2 hr before hemodialysis. Serial arterial and venous blood samples as well as outflowing dialysate samples were collected and analyzed by high-pressure liquid chromatography for dyphylline. The extraction efficiency of the hollow-fiber dialyzers averaged 44.6%. The mean dialysis clearance was 108.7 ml/min which compares favorably to the 57 ml/min metabolic clearance of the drug. A mean of 278.6 mg or 28.34% of the administered dose was recovered in the dialysate during the 4-hr dialysis interval. Half-lives for dyphylline during dialysis ranged from 3.43 to 7.62 hr. The off-dialysis half-lives for two of the four patients studied on a separate occasion were 10.6 and 13.2 hr. The overall clearance calculation projects an average half-life reduction of approximately 65% during hemodialysis. We conclude that dyphylline is dialyzable. Hemodialysis patients receiving dyphylline treatment may require a dosage regimen alteration. In addition, hemodialysis may be useful for the treatment of dyphylline overdose because of its effectiveness in accelerating the removal of the drug.

Urinary excretion of dyphylline in humans.

The pharmacokinetics and urinary excretion of a single dyphylline dose were studied in five normal volunteers. The mean dyphylline half-life was 1.8 +/- 0.2 hr; the mean total body clearance rate and mean renal clearance rate were 333 +/- 62 and 276 +/- 52 ml/min, respectively; and the mean volume of distribution was 0.8 +/- 0.2 liter/kg. In the urine, 83 +/- 5% of the dose was excreted as unchanged drug, and theophylline was not detected. Dyphylline doses of 19--27 mg/kg, resulting in peak serum dyphylline concentrations of 19.3--23.5 micrograms/ml, were tolerated well by four subjects. One subject had a severe headache following a 28-mg/kg dose, associated with a peak serum dyphylline concentration of 36.4 micrograms/ml. This study confirms speculation that dyphylline is not metabolized to theophylline in vivo.