Use of dodecyl sulfate as an esterase inhibitor before gas-chromatographic determination of labile beta-adrenoceptor blocking drugs.

Sodium dodecyl sulfate (SDS) was introduced as an esterase inhibitor in the determination of two extremely labile, ultrashort-acting beta-blockers-esmolol and flumolol--in whole blood. SDS was much more efficient than previously used agents in preventing hydrolysis. The assay comprises solvent extraction, perfluoroacylation, and capillary gas-chromatography with electron-capture detection. The limit of detection (the concentration at which the coefficient of variation is 10-15%) for the drugs is 5 nmol/L of whole blood.

Electron-capture-gas chromatographic determination of atenolol in plasma and urine, using a simplified procedure with improved selectivity.

A sensitive gas chromatographic method for the quantitative analysis of atenolol in human plasma and urine is described. Atenolol is extracted with dichloromethane containing heptafluorobutanol to improve the extraction ability. Derivatization with trifluoroacetic anhydride in diethyl ether gives a bistrifluoroacetyl derivative which is more selectively detected by an electron-capture detector than is the corresponding heptafluorobutyryl derivative. The method allows determination down to 20 nmol/l (5 ng/ml) in 1 ml of sample with a relative standard deviation below 10%.

Selected ion monitoring of metoprolol and two metabolites in plasma and urine using deuterated internal standards.

A highly sensitive and specific quantitative assay for metoprolol and two of its metabolites, containing an unchanged 2-hydroxy-4-isopropylaminopropoxy sidechain, has been developed. The compounds are isolated from the alkalized sample (plasma or urine) by extraction with dichloromethane, and converted to trifluoroacetyl derivatives by reaction with methyl-bis-(trifluoroacetamide). The reaction mixture is gas chromatographed on an OV-17 column and each substance is assayed by electron impact mass spectrometry using selected ion monitoring, and quantified by comparing the intensity of fragment ion m/z 266 with the intensities of corresponding fragment ions from the deuterated internal standards (m/z 270 and 271). It is possible to determine concentrations as low as 1 nmol l-1 (0.3 ng ml-1) in 1 ml of sample with relative standard deviation of less than 10%.

Assay of prenalterol in plasma and urine by gas chromatography-mass spectrometry.

A sensitive and selective method for the quantitative analysis of prenalterol in plasma and urine is described. Prenalterol and the internal standard, deuterated prenalterol, are extracted with diethyl ether at pH 9.9 under salting-out conditions. Derivatization is performed by means of pentafluoropropionic anhydride in toluene before separation in the gas chromatograph. Detection and quantification of the triacyl derivatives are done by mass spectrometry in the selected ion monitoring mode. The method allows determination of concentrations down to 5 nmol/l (1 ng/ml) in 1 ml of sample, with a relative standard deviation below 10%.

Monitoring of S- and R-tocainide in human plasma after heptafluorobutyrylation, separation on Chirasil-Val and electron-capture detection.

The conditions for the heptafluorobutyrylation of tocainide have been studied. An almost instantaneous reaction was obtained with 0.01% of heptafluorobutyric anhydride in toluene at 40 degrees C. Higher anhydride concentration caused degradation of the initially formed derivative, mainly by the loss of water, as shown by mass spectral analysis. Tocainide was isolated from plasma by extraction into dichloromethane at alkaline pH. Gas chromatographic separation was performed with a fused-silica capillary column coated with a methyl silicone gum. The enantiomers were separated on a glass capillary column coated with Chirasil-Val. Upon analysing 0.1 ml of plasma eight times the precision was 4.7% at the 10 mumol/1 level for the S-form of tocainide.

Pharmacokinetics of pafenolol after i.v. and oral administration of three separate doses of different strength to man.

The pharmacokinetics of pafenolol were evaluated in 12 healthy subjects after administration of three single IV doses (5, 10, and 20 mg) and three oral single doses (25, 50, and 100 mg). The drug was discontinuously absorbed. A first peak was observed 0.5 to 1.5 h after dosing and a second higher maximum concentration was noted 3 to 5 h after the administration in the majority of the experiments. The mean systemic availability increased from 27 +/- 5 per cent for the oral 25 mg dose to 46 +/- 5 per cent for the 100 mg dose, i.e., an increase of about 70 per cent (p less than 0.05). The half-life of distribution varied between 5 and 6 min and the apparent volume of distribution (Vz) was about 1.11 kg-1. The distribution was linear in the IV dose range studied. Total body clearance was about 300 ml min-1. About 50 per cent of the systemically available dose was excreted unchanged via the kidneys. Total body clearance decreased by about 13 per cent (p less than 0.05) by increasing the dose from 5 to 20 mg IV possibly because of reduced renal elimination. Mean terminal t1/2 of the IV dose was approximately 3.5 h. The corresponding t1/2 of the oral dose was approximately 6 h indicating absorption rate-limited kinetics of the oral dose.

Pharmacokinetics of a single intravenous and oral dose of pafenolol--a beta 1-adrenoceptor antagonist with atypical absorption and disposition properties--in man.

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 microCi [3H]pafenolol. The plasma concentration-time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 +/- 0.2 and 3.7 +/- 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 +/- 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t1/2 lambda 1 was 6.6 +/- 1.8 min. The volumes of distribution were Vc = 0.22 +/- 0.08 liter/kg, Vss = 0.94 +/- 0.17 liter/kg, and Vz = 1.1 +/- 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 +/- 5.1% of the given dose and in the feces to 23.8 +/- 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 +/- 5.9 and 67.0 +/- 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 +/- 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 +/- 31, 31 +/- 15, and 95 +/- 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 +/- 0.3 hr for the iv dose and 6.7 +/- 0.7 hr for the oral dose.