Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients.

The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction. Disposition after i.v. administration was described by a clearance of 0.54 l.min-1, central compartment volume of 14.8 l, distribution rate constant 0.092 min-1, and an elimination rate constant of 0.0044 min-1. The corresponding estimates after i.m. administration were 0.324 l.min-1, 34.1 l, 0.035 min-1, and 0.0018 min-1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC50 of 12.8 ng.ml-1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng.ml-1, and 9 min. Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats.min-1, with an EC50 of 176 ng.ml-1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats.min-1, 250 ng.ml-1, and 3 min. The optimal plasma concentration of thiazinamium was about 100 ng.ml-1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats.min-1.

Clinical pharmacokinetics of intramuscular thiazinamium methyl sulfate.

The disposition of the quaternary ammonium compound thiazinamium methyl sulfate is described after intramuscular injection in humans. The plasma concentration-time curves could be resolved into two exponential components, suggesting an open two-compartment model with absorption phase. Absorption was found to be extremely fast. Peak concentrations were always reached within 20 min, but in the majority of cases they were found to be between 6 and 10 min. Occasionally, the first sample (t = 3 min) proved to contain the highest concentration. Apparently the high solubility of the drug in the interstitial fluid is of prime importance for rapid absorption. Injection technique and the injection site seemed to be important for the final profile of the plasma concentration-time curve. Distribution was found to be very fast as well, with a half-life of approximately 20 min, and the apparent volume of distribution for the central compartment was about 40-60 l. Muscle activity and hence increased capillary blood flow during the distribution phase may result in a second peak in the plasma concentration-time curve. The distribution phase is followed by an elimination phase with a much longer half-life (mean value 375 min) and a volume of distribution of approximately 200-400 l. The total body clearance for thiazinamium methyl sulfate was found to be high (mean value about 800 ml/min), suggesting an active excretion process.

Metabolism and excretion of the quaternary ammonium compound thiazinamium methylsulfate (Multergan) in man. I. Parenteral administration.

The quaternary ammonium compound thiazinamium was found to be metabolized by sulfoxidation solely. No ring hydroxylation products, nor demethylation products (e.g. promethazine) could be found. Thiazinamium sulfoxide was found both in urine and bile, but thiazinamium is-after parenteral administration - mainly excreted in the unchanged form. After intravenous injection about 40% of the dose was excreted, unchanged, in the urine. The excretion was very rapid and almost complete within eight hours. About 9% of the dose was excreted in the urine in the form of thiazinamium sulfoxide cations. After intramuscular injection virtually the same figures for urinary excretion were found. No correlation could be observed between urine production or pH and the amount of drug excreted in urine. In a study involving bile-fistula patients it was found that both thiazinamium cations and thiazinamium sulfoxide cations are excreted to a considerable extent in bile. The amount of unchanged drug in bile was almost equal to that in urine, but the amount of sulfoxide was slightly higher.

Metabolism and excretion of the quaternary ammonium compound thiazinamium methylsulfate (Multergan) in man. II. Oral and rectal administration.

In this study it is shown that biotransformation of thiazinamium, when given orally, does not differ qualitatively from the pattern found after parenteral administration. However, quantitatively both the metabolism and excretion patterns are considerably different from those after intravenous injection. The renal clearance accounted for 256 +/- 136 ml.min-1 (mean +/- SD). This value is higher than glomerular filtration, which may be indicative of an active excretion process. Hepatic clearance (biotransformation and biliary excretion of unchanged cation) was 537 +/- 495 ml.min-1 (mean +/- SD). Hepatic clearance was found to correlate negatively with bioavailability. The ratio between unchanged drug and the only metabolite, the sulfoxide, in urine was about I:0.9. This is substantially different from that found after parenteral administration (ca. I:0.2), which may imply that a 'first-pass effect' occurs. It was estimated that ca. 50% of the absorbed amount was metabolized during the first liver passage. The fate of thiazinamium after rectal administration in Witepsol HI5 suppositories shows several similarities with that after oral administration. The ratio between unchanged drug and metabolite in urine in this case was ca. I:0.8, indicating that also after rectal administration a 'first-pass effect' occurs, now to a degree of ca. 35%.

First-pass effect after rectal administration of thiazinamium methylsulfate.

The absorption and metabolism of the quaternary ammonium compound thiazinamium methylsulfate were studied in humans using plasma concentration data and urinary excretion measurements. After giving a dose of 150 mg in suppositories, the relative bioavailability was 5.8 +/- 3.2 (SD) % of the dose, comparable to the values obtained following oral administration. The degree of first-pass effect observed after rectal administration was comparable with that after oral administration.

Determination of oxyphenonium bromide in plasma and urine by means of ion-pair extraction, derivatization and gas chromatography-electron-capture detection.

A sensitive and selective method for the determination of the quaternary ammonium compound oxyphenonium bromide (Antrenyl), a drug with strong anticholinergic properties, in human plasma and urine is described. The method is based on ion-pair extraction of the cation with perchlorate, a re-extraction according to ion-pair principles with tetrapentylammonium as the counter ion, hydrolysis to cyclohexylphenylglycolic acid, derivatization of this acid to its pentafluorobenzyl ester and determination of the ester by gas chromatography and electron-capture detection. Quantitation is possible down to 2 ng/ml of oxyphenonium bromide using 1 ml of plasma and down to 200 ng/ml using 0.1 ml of urine. The method described can also be applied to other anticholinergic drugs with an ester function.

Variations in the bioavailability of thiazinamium methylsulfate.

Bioavailability after oral administration of the anticholinergic drug thiazinamium methylsulfate (Multergan), a phenothiazine derivative with a quaternary ammonium group in the molecule, has been studied in patients and volunteers by measuring the drug concentrations in plasma or the excretion of the parent drug in urine. The relative bioavailability as compared to intramuscular injection seems to be of the order of 10%. Much more of the drug is absorbed, however, but is metabolized during the first liver passage. Moreover, there seems to be a substantial interindividual variation in the bioavailability of the drug. Studies in a group of eight volunteers showed that there is also a substantial intraindividual variation, but its magnitude is smaller than that of the interindividual variation.

Determination of low cencentrations of the quaternary ammonium compound thiazinamium methylsulphate in plasma and urine.

A sensitive and selective method for the quantitative determination of the quaternary ammonium antiacetylcholine-compound thiazinamium methylsulphate (Multergan) in plasma and urine is described. The procedure is based on ion pair extraction of the compound with iodide as the counter ion. This is followed by gas chromatography using an alkali flame ionization detector. The detection limit is 2 ng ml-1 with a recovery of 88-0 +/- 6-2% from plasma, 91-4 +/- 4-6% from urine. The described method can also be applied to other quaternary ammonium compounds.