Pharmacokinetics in the human of a new synthetic vasopressin and oxytocin uterine antagonist.

The pharmacokinetics in the human of 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin (dE-TVT), was studied after iv and intranasal administration in 11 subjects at 12 experiments each route. The plasma concentration of the analogue was analysed by means of an arginine vasopressin antibody, which cross-reacted with dE-TVT to 4.7%. When given intravenously as bolus injection (10 nmol/kg/body weight), the total body clearance amounted to 0.623 +/- 0.099 (SEM) l/h kg and the half-life to 16.2 +/- 2.4 min. After intranasal administration (100 nmol/kg/body weight), the bioavailability was 10.5 +/- 2.9%. Peak concentrations in plasma appeared 2-8 min after iv and 10-45 min after intranasal administration. At the end of an observation period of 2 h measurable amounts in plasma were still found in one of the iv and seven of the intranasal experiments. It is concluded that the moderately long half-life is suitable for the treatment of hospitalized patients in premature labour where promising results with intravenous infusion (50 micrograms/min) of dE-TVT have been obtained. It is still uncertain whether or not the absorption of dE-TVT is sufficient for intranasal administration to out-patients with uterine hyperactivity in late pregnancy and to patients with primary dysmenorrhoea, where significant relief of symptoms were seen after iv administration (10 micrograms/kg body weight).

Pharmacokinetics of terbutaline after parenteral administration.

The basal model-independent pharmacokinetic parameters body clearance (CL), renal clearance (CLR), mean residence time (MRT), and volume of distribution in steady state (Vss) were calculated from concentrations of terbutaline in plasma and amounts in urine after intravenous administration of the drug in 19 healthy men. The data used were from three separate studies. Measurements up to 12 h gave estimated values for CL from 136 mL/min to 340 mL/min, for CLR from 82 mL/min to 192 mL/min, for MRT from 1.5 h to 5.6 h, and for Vss from 24 L to 73 L. In 6 subjects, there were measurements for longer than 24 h that could be used to calculate the parameters. Body clearance was now found to vary between 165 and 270 mL/min. MRT between 7.3 and 11.7 h, and Vss between 83 and 140 L. The evaluations indicate that CL will be overestimated and MRT and Vss underestimated from data only up to 12 h.

Absorption of enprofylline from the gastrointestinal tract in healthy subjects.

Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1-4 mg/l, i.e. in the assumed "therapeutic interval" according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean +/- SEM) were 32.5 +/- 8.7, 13.3 +/- 2.5, and 157 +/- 23 min.

Enprofylline kinetics in healthy subjects after single doses.

The kinetics of enprofylline, a novel antiasthmatic xanthine derivative, were studied. Eight healthy subjects received three different single enprofylline doses, 0.5, 1, and 1.5 mg/kg, injected as an infusion over 10 min. Plasma and urine levels of unchanged enprofylline were observed 3 to 7 and 21 to 24 hr after dosing. Plasma t 1/2 varied among individuals from 1.2 to 1.9 hr. Volume of distribution (V beta or area) and volume of distribution at steady state (V ss) averaged 0.57 and 0.511 X kg-1. Total clearance averaged 0.25 l X hr-1 X kg-1. Renal clearance ranged from 200 to 400 ml X min-1, indicating a large contribution by active tubular secretion. The mean recovery of unchanged drug in the urine was 89%. Thus, unlike theophylline, enprofylline was eliminated mainly by the kidney.

Absorption of sustained-release theophylline tablets.

Three different sustained-release tablets of theophylline (Theo-Dur, Phyllocontin continus, Euphyllin Retard) and an oral elixir of aminophylline were administered to 12 healthy volunteers according to a crossover scheme. Plasma concentration of theophylline was monitored for 33 h after each administration using an HPLC reversed-phase method. The mean values and SD for total body clearance (0.054 +/- 0.010 l/[h X kg]), elimination half-life (6.0 +/- 1.2 h), and volume of distribution (0.455 +/- 0.046 l/kg) were calculated from the plasma concentration curves after the administration of elixir. The mean bioavailability of Theo-Dur was 94%, Phyllocontin continus 88%, and Euphyllin Retard 84%. The absorption was faster from Phyllocontin continus than from Theo-Dur or Euphyllin Retard. The time of peak concentration varied considerably after Euphyllin Retard but was less fluctuating among the subjects after Phyllocontin continus or Theo-Dur. In some subjects an extremely delayed peak (up to 24 h after administration) was observed after Euphyllin Retard.

Intravenous administration of enprofylline to asthmatic patients.

In 6 asthmatic patients, the possibility of obtaining a steady state plasma level of 5 mg/l of enprofylline by administration of two constant rate infusions was examined. The simulated plasma concentration curves, based on information from preassessment of individual pharmacokinetic parameters, were in good agreement with the plasma levels obtained. The side-effects and bronchodilatation produced by enprofylline were compared to those obtained with theophylline at a steady state level of 15 mg/l. Enprofylline and theophylline caused a mean maximal increase in FEV1.0 of 14% and 2.6% per mg/l in plasma, respectively. Side-effects, headache, nausea and vomiting, became pronounced in 2 patients in whom the plasma enprofylline level was about 6 mg/l. No other serious adverse reaction was seen. It is suggested that enprofylline should be further evaluated as a possible anti-asthmatic drug.

Extrapulmonary effects of terbutaline during prolonged administration.

Hand tremor, heart rate, and electrolyte, plasma (pl) insulin, blood (bl) glucose, and pl terbutaline levels were measured in 11 healthy men during infusion and oral administration of terbutaline. Infusion of terbutaline (250 micrograms) was followed by increases in pl insulin concentration and bl glucose and by a decrease in pl K. Similar metabolic changes were seen on day 1 of oral terbutaline (5 mg x 3). Heart rate was moderately increased by terbutaline over the entire period (13 days) or oral dosing. Hand tremor always increased after terbutaline, but to a lesser degree on days 4 and 13 than after the first oral dose. On day 13 there was a very small increase in pl insulin and no reduction in pl K; bl glucose increased slightly from an elevated basal level. Pl terbutaline was of similar maximum concentrations on days 1 and 13, indicating that the tolerance was mediated through reduced response of the effector organs.

Terbutaline depot tablets in asthma. A clinical evaluation.

A sustained release preparation of terbutaline sulphate has been formulated (Bricanyl depot tablets) in order to extend the duration and accordingly change the dosage regimen to twice a day. This presentation gives a summary of a clinical trial performed in order to study effect and side effects of terbutaline depot tablets 7.5 mg twice a day compared to terbutaline tablets 5 mg three times a day. Patients suffering from perennial asthma and with daily requirement of asthma medicine were accepted for the study. The trial was a double-blind cross-over, double dummy and randomized. The tablets were given in two consecutive periods of 7 day's duration each. The effect of terbutaline depot tablets was equal to the effect of the ordinary terbutaline tablets. The indication for using depot tablets in the basic treatment of bronchial asthma is a better patient compliance due to medication twice a day. Furthermore in patients with unstable bronchial asthma and in patients with morning dips in PEF the more stable plasma concentration may perhaps keep the patients in a more steady state.

Absorption of theophylline from conventional and sustained-release tablets.

Healthy adults were treated in periods of 4 days with fast-dissolving theophylline tablets (Oxyphyllin, Draco, Sweden) and sustained-release tablets (Theo-Dur, Draco, Sweden). To some of the volunteers a single dose of i.v. aminophyllamine was administered. The absorption of theophylline, calculated from single dose administration of uncoated tablets (Oxyphyllin) was completed within 2 hrs, whereas the absorption from sustained-release tablets (Theo-Dur) continued for 12 hrs. There was no significant difference in bioavailability between aminophylline i.v., Oxyphyllin tablets and Theo-Dur tablets. The slow-release tablet gave a stable plasma level in steady state that implies the possibility of using 12-hr dosage intervals and still achieving a stable theophylline concentration in steady state with a small difference between peak and trough concentrations. This investigation shows that it is possible to simulate the plasma concentration of theophylline in steady state by means of oral administration, using the simple one-compartment model calculated from data registered after a single i.v. dose.

Absorption of theophylline from conventional and sustained-release tablets.

Healthy adults were treated in periods of 4 days with fast dissolving theophylline tablets (Oxyphyllin, Draco, Sweden) and sustained-release tablets (Theo-Dur, Draco, Sweden). To some of the volunteers, a single dose of i.v. aminophyllamine was administered. The absorption of theophylline, calculated from a single dose administration, of uncoated tablets (Oxyphyllin) was completed within 2 hours, whereas the absorption of sustained-release tablets (Theo-Dur) continued during 12 hours. There was no significant difference in bioavailability between aminophylline i.v., Oxyphyllin tablets and Theo-Dur tablets. The slow release tablets gave a stable plasma level in steady state that implies the possibility of using 12-hour dosage intervals and still achieve a stable theophylline concentration in steady state with a small difference between peak and trough concentrations. This investigation shows that it is possible to simulate the plasma concentration of theophylline in steady state by means of oral administration, using the simple one-compartment model calculated from data registered after a single i.v. dose.

Pharmacokinetics of whole and half Theo-Dur tablets.

The bioavailability and absorption patterns of whole and divided sustained-release theophylline tablets, Theo-Dur, were investigated. Both whole and divided tablets were well absorbed. The rates of absorption differed. The mean absorption time for whole tablets was 5.7 h and for divided tablets 4.2 h. The influence of these differing mean absorption times on the appearance of the serum curves is negligible, and the sustained action is maintained also after breaking the tablets. The present investigation shows that Theo-Dur tablets can be broken for dosage convenience, still maintaining the sustained action.