sq-14551 and Hypertension

A new and sensitive HPLC method has been developed for the determination of captopril plus its disulfide metabolites (total captopril) in human plasma. Captopril disulfides and the drug covalently bound to protein were reduced with sodium borohydride to captopril. After liquid-liquid extraction, captopril was treated with o-phthalaldehyde in the presence of D-phenylalanine. The fluorescent derivative of captopril was measured by HPLC using a C-18 reversed phase column with fluorescence detection at the excitation and emission wavelengths of 235 nm and 440 nm, respectively. The mobile phase consisted of a methanol-acetonitrile-phosphate buffer (0.02 mol.L-1, pH 6.4) mixture (30:30:135, v/v), and was set at a flow rate of 1 ml.min-1. The linear range of the assay was between 5 ng.ml-1 (lower limit of quantitation) and 300 ng.ml-1 for total captopril in plasma. The method was successfully applied to determine plasma concentrations of captopril plus its disulfide metabolites in hypertensive patients and was demonstrated to be suitable for the therapeutic drug monitoring.

Topics: Antihypertensive Agents; Captopril; Chromatography, High Pressure Liquid; Humans; Hypertension

We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 micrograms X ml-1 vs 0.181 micrograms X ml-1) and the concentrations of the disulfides 4 times higher (3.62 micrograms X ml-1 vs 0.924 micrograms X ml-1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46 +/- 19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37 +/- 7 mmHg and 24 +/- 9 mmHg respectively, occurring 6 h after the dose, compared with 8 +/- 7 and 8 +/- 1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.

Topics: Adult; Blood Pressure; Captopril; Female; Half-Life; Humans; Hypertension; Kidney Failure, Chronic; Kinetics; Male; Middle Aged; Renal Dialysis

Topics: Adrenergic beta-Antagonists; Captopril; Diuretics; Humans; Hypertension; Kidney Diseases