RESUMEN
An HPLC method for the simultaneous determination of sulfinpyrazone and its p-hydroxy, sulfone, sulfide and p-hydroxysulfide metabolites in human plasma and urine samples was developed. Optimization with regard to sample preparation and chromatographic conditions was investigated. In the final procedure samples were acidified with HCl, extracted with a 1 + 1 (vol/vol) mixture of 1-chlorobutane and chloroform; urine extracts were re-extracted with citrate buffer (pH 4.5). HPLC was performed on reversed phase (RP 8) columns with a 48 + 52 (vol/vol) mixture of ethanol and citrate buffer (pH 2.5) as the mobile phase. The lower limit of detection for sulfinpyrazone and the sulfide metabolite is 10 ng/ml, for the other metabolites it is 50 ng/ml. An example of application of this procedure to pharmacokinetic studies in a volunteer receiving a single oral dose of sulfinpyrazone is given.
Asunto(s)
Sulfinpirazona/análisis , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Humanos , Cinética , Solventes , Espectrofotometría Ultravioleta , Sulfinpirazona/sangre , Sulfinpirazona/orinaRESUMEN
Comparison of oral and i.v. administration of sulphinpyrazone (10 mg/kg) to rabbits showed that the oral route was associated with an incomplete bioavailability and a six-fold greater formation of the active sulphide metabolite. The bile was an important route of elimination of unchanged sulphinpyrazone in rabbits (18% of an i.v. dose in four hours). Only small amounts of the sulphide appeared in the bile after i.v. administration. Pretreatment with oral antibiotics decreased the area under the plasma concentration-time curve (AUC) for the sulphide but increased that of the parent drug. Excretion of the p-hydroxysulphide metabolite in urine was decreased 30-fold by antibiotic treatment. The contents of the caecum showed the greatest capacity for sulphinpyrazone reduction in vitro. The liver possessed a slight ability to reduce sulphinpyrazone in vitro under anaerobic, but not aerobic, conditions. The gut bacteria are the main site of reduction of sulphinpyrazone to the active sulphide metabolite in the rabbit. These findings contrast with those obtained for sulindac which was reduced extensively under both aerobic and anaerobic conditions by rabbit-liver soluble fraction in vitro. The sulphide metabolites of both sulphinpyrazone and sulindac were oxidized to the parent drug by rabbit-liver microsomes.
Asunto(s)
Sulfinpirazona/metabolismo , Administración Oral , Animales , Antibacterianos/farmacología , Bilis/metabolismo , Cromatografía Líquida de Alta Presión , Femenino , Técnicas In Vitro , Inyecciones Intravenosas , Intestinos/microbiología , Hígado/metabolismo , Masculino , Oxidación-Reducción , Conejos , Sulfinpirazona/sangre , Sulfinpirazona/orinaRESUMEN
1 High pressure liquid chromatographic assays for the estimation of sulphinpyrazone and its sulphide, sulphone and p-hydroxy metabolites in plasma and urine are described. 2 Five normal volunteers received 200 mg and 400 mg sulphinpyrazone orally. Sulphinpyrazone was rapidly absorbed and eliminated with a half-life of approximately 4 h irrespective of dose. Peak plasma concentrations and area under the plasma concentration-time curves (AUC) were consistent with linear pharmacokinetic behaviour. 3 Plasma concentrations of the sulphone were low and peaked before those of the sulphide; its mean half-life was 3.1 h. The sulphide, which may be the sulphinpyrazone metabolite with activity on platelets, was eliminated with a mean half-life of 13.4 h. The AUC increases with dose of both metabolites suggested non-linearity. 4 Approximately 45-50% of the administered dose was eliminated in the urine as unchanged drug or as sulphone or p-hydroxy-sulphinpyrazone. The sulphide metabolite was not detected in the urine. The renal clearance of sulphinpyrazone was approximately 18 ml min-1 and that for the sulphone was similar. Sigma minus plots of the urinary excretion yielded half-lives of 3.5 h for the sulphone and 1 h for p-hydroxy-sulphinpyrazone.
Asunto(s)
Sulfinpirazona/metabolismo , Adulto , Biotransformación , Proteínas Sanguíneas/metabolismo , Femenino , Semivida , Humanos , Hidroxilación , Cinética , Masculino , Sulfuros/metabolismo , Sulfinpirazona/sangre , Sulfinpirazona/orina , Sulfonas/metabolismoRESUMEN
A rapid, senstivie, and specific high-performance liquid chromatographic method is described for the quantitative analysis of sulfinpyrazone and its sulfone and p-hydroxy metabolites in plasma and urine. The method uses two different procedures for sample preparation: (1) a rapid and convenient procedure using a single extraction with 1-chlorobutane and subsequent back-extraction into sodium hydroxide solution for the analysis of sulfinpyrazone and its sulfone metabolite, and (2) a more time consuming procedure using triple extraction with ethylene dichloride, a buffer wash, and back extraction into the base for the additional analysis of the p-hydroxy metabolite. The lower limit of sensitivity for fulfinpyrazone is 50 ng/ml. Concentrations of sulfinpyrazone between 0.05 and 0.1 and 50 micrograms/ml were measured with an average coefficient of variation of 3.9%, ranging from 1.5 to 6.1%.
Asunto(s)
Sulfinpirazona/análogos & derivados , Sulfinpirazona/sangre , Butanos , Cromatografía Líquida de Alta Presión/métodos , Dicloruros de Etileno , Humanos , Masculino , Sulfinpirazona/metabolismo , Sulfinpirazona/orina , Sulfonas/sangre , Sulfonas/orinaRESUMEN
The disposition and metabolism of sulfinpyrazone have been studied after oral administration of 100 mg 14C-labelled drug to two male volunteers. The results confirmed earlier observations on the kinetics and biotransformation of the drug in man. Additionally, four new metabolites were identified and quantified, i.e., the sulfide analogue G 25 671 of sulfinpyrazone (Anturano), the p-hydroxy-sulfide G 33 378, the p-hydroxy-sulfone CGP 17 385 and the C(4)-glucuronide of the sulfide. In plasma, the area under the concentration-time curve (0--24 h) of sulfinpyrazone was, on an average, 61.7% of that of total 14C-substances. The AUC-value for the sulfide and the sulfone corresponded to 13.4 and 6.0%, respectively. The other, specifically measured plasma metabolites (p-hydroxy-sulfin-pyrazone, p-hydroxy-sulfide, p-hydroxy-sulfone and 4-hydroxy-sulfinpyrazone) accounted for only 1.6% or less of total AUC. Almost no sulfide was excreted in the urine. The compound was transformed to its C(4)-glucuronide, a reaction common to drugs of the dioxo-pyrazolidine series. The appearance of the sulfide in plasma may be clinically important, since this metabolite shows a strong inhibitory effect on platelet aggregation in various in vitro experimental systems.
Asunto(s)
Sulfinpirazona/metabolismo , Adulto , Biotransformación , Radioisótopos de Carbono , Heces/análisis , Humanos , Masculino , Persona de Mediana Edad , Sulfinpirazona/sangre , Sulfinpirazona/orinaRESUMEN
The kinetics of anturan excretion was studied. Experiments were carried out on ten healthy volunteers. The drug was given orally once applying three different doses: 100, 200, 400 mg. The contents of the drug in urine were determined by means of the modified method worked out by Wallace. It was found about 42 per cent of the dose was excreted with urine in an unchanged form. The process of anturan excretion may be described according to the one-compartment open kinetic model. The half-life of excretion is 3.5 hours, the excretion constant is 0.20. The formula showing the course of anturan excretion in time has been given. Five examples of the quantitative exposure test have been proposed; they allow the calculation of the absorbed drug dose and thus the degree of poisoning. The test can be also helpful in controlled therapy.
Asunto(s)
Sulfinpirazona/orina , Femenino , Semivida , Humanos , Cinética , Masculino , Factores Sexuales , Factores de TiempoRESUMEN
A selective and sensitive gas chromatographic method for simultaneous determination of sulfinpyrazone and two of its metabolites (the para-hydroxylated metabolite and the sulfone metabolite) in biological fluids using alkali flame ionization detection (AFID), electron capture detection (ECD) and mass fragmentographic detection is described. The compounds are extracted from the samples, methylated and separated on 2% OV-17 or 3% OV-225 columns. Phenylbutazone is used as internal standard. Standard curves are linear. The coefficient of variation at 10 microgram/ml of sulfinpyrazone in plasma was shown to be 1.8% (AFID), and the detection limits were 0.1 microgram/ml (AFID) and 10 ng/ml (ECD). Mass spectra of the methylated compounds are shown and serum concentration curves after oral administration of 100 mg sulfinpyrazone to two persons are determined together with the excreted amounts of drug and metabolites.
Asunto(s)
Cromatografía de Gases y Espectrometría de Masas/métodos , Sulfinpirazona/sangre , Ionización de Llama , Humanos , Sulfinpirazona/farmacología , Sulfinpirazona/orinaRESUMEN
A method for the quantitative determination of sulphinpyrazone in plasma and urine is described. The drug is extracted from the acidified aqueous phase with 1-chlorobutane-ethylene dichloride (4:1) and separated from its metabolites by high-performance liquid chromatography on 5-mum LiChrosorb using dichloromethane-ethanol-water-acetic acid (79.1:19:1.9:0.002) as the mobile phase. The sensitivity limit is 0,2mug/ml using a 1-ml sample. Examples of applications are given.