No abstract

The pharmacokinetics of dapsone (DDS) and monoacetyldapsone (MADDS) following an oral dose of 150 mg DDS were studied in sixteen patients with dermatitis herpetiformis and seven normal subjects. No differences in DDS disposition were observed between the two groups. The maintenance dose of DDS for individual patients was not significantly correlated with jejunal biopsy morphology, DDS or MADDS half-lives, or the area under the plasma concentration-time curves for DDS or MADDS. DDS plasma protein binding was normal in patients and did not apparently determine the concentration of DDS in skin biopsies, for which the skin/plasma DDS concentration ratio was approximately unity. There was no undue representation of acetylator phenotype in the patient group and no correlation between maintenance dose and MADDS/DDS ratio was noted. The determinants of the maintenance DDS dose have not been found. This may relate to pharmacodynamic differences, but alternatively the concentration of oxidative metabolites rather than DDS or MADDS could be responsible for the therapeutic activity in dermatitis herpetiformis.

A high performance thin layer chromatographic assay for dapsone is described with a minimum level of detection of 20 ng ml-1 which is suitable for the study of dapsone pharmacokinetics in plasma and saliva. 100 mg dapsone was administered orally to seven normal adult volunteers, the mean plasma pharmacokinetic parameters were: alpha = 0.23 h-1; beta = 0.0236 h-1, and t1/2 beta = 30.2 h. Dapsone is also eliminated into the saliva and the t1/2 may be determined via its estimation in saliva. It is 73% bound to plasma protein and the saliva/plasma concentration ratio was found to be 27%. In two subjects the free plasma dapsone concentration was identical to the simultaneous salivary dapsone concentration. Therefore the salivary dapsone concentration is a measure of the free plasma fraction of dapsone. Saliva/plasma dapsone concentration ratios show no time or concentration dependence and little inter-individual variation but are unsuitable for acetylator phenotype determination because monoacetyldapsone is not eliminated in the saliva.

The pharmacokinetics of high-dose IV melphalan (140 or 220 mg m-2) were studied after 12 administrations in 10 children (aged 2.5-16 years) undergoing chemotherapy for either neuroblastoma or Ewing's tumour. To assess whether a simpler and less expensive nitrobenzylpyridine (NBP) spectrophotometric assay for alkylating activity was a satisfactory alternative to high-pressure liquid chromatography (HPLC), the plasma melphalan concentration was estimated by both methods in five cases. Analysis of the disposition of melphalan gave a mean half-life of 1.3 +/- 1.0 (SD) h, clearance 18.4 +/- 9.4 l X h-1 X m-2, and apparent volume of distribution 26.3 +/- 18.0 l X m-2. These pharmacokinetic parameters were similar to those found in adults: no correlation was found between any parameter and age or glomerular filtration rate. NBP alkylating activity determinations yielded consistent results and good correlation with plasma melphalan concentration. However, concordance analysis indicated a consistent bias, the NBP assay always giving lower estimates of plasma melphalan concentration: HPLC assay therefore remains the method of choice for determining plasma melphalan pharmacokinetics.

A simple and robust analytical reversed-phase high-performance liquid chromatography method was developed and validated for simultaneous chromatographic elution of three cardiovascular drugs, namely clopidogrel, aspirin (ASP) and atorvastatin. The method was developed in rat plasma and dosage formulation with high-quality chromatographic separation between the drug peaks by using a stainless steel analytical column thermo beta-basic, C18 (25 × 0.46 cm, 5 µm). The system was operated at 25°C using a mobile phase consisting of acetonitrile and phosphate buffer (pH 3.0) in the gradient ratio at a flow rate of 1 mL min(-1) with ultraviolet detection monitored at 232 nm. The parametric statistics, i.e., correlation coefficient of 0.999, was assessed for all the drugs having linearity over the tested concentration range (10-10,000 ng mL(-1)) in rat plasma using an unweighted calibration curve. The accuracy of samples for six replicate measurements at lower limit of quantitation level was within limit. The method was applicable for the quality control of the mentioned drugs in raw material, bulk drug and pharmaceutical formulations as well as in pharmacokinetic studies.