Conditions for the extractive alkylation of eight sulphonylurea hypoglycemic drugs have been evaluated. Extractive methylation of the compounds was achieved within 90 min using tetrabutylammonium as counter-ion (0.1 M at pH = 6.9) with 5% methyl iodide in dichloro-methane as organic phase. Mass spectral analysis showed derivatives methylated at the sulphonamide nitrogen. A higher pH or use of tetrapentylammonium as counter-ion caused hydrolysis of the sulphonylureas. The derivatives showed a high electron-capture response with minimum concentrations detectable in the range 1-4 x 10(-16) moles sec-1. Therapeutic plasma concentrations of glipzide and tolbutamide were determined by direct extractive methylation of the compounds from the plasma sample. The glipizide derivative was determined by electron-capture gas chromatography down to about 20 ng/ml in a 0.5-ml plasma sample. The relative standard deviation at the 0.2 microgram/ml level of glipizide was 6% (n = 6). The corresponding figure in the determination of tolbutamide at the 10 microgram/ml level was 3% (n = 10).