Anomalous Results of Studies on Drug Interaction in Man

Abstract

Disulfiram inhibited antipyrine metabolism reproducibly in three experiments utilizing three different groups of normal human volunteers. In these experiments disulfiram in a dose of 3.5 mg/kg body weight was given orally twice daily for 4 consecutive days and in two subsequent experiments for 10 consecutive days. In each experiment the mean antipyrine half-life was prolonged and the mean metabolic clearance rate of antipyrine was shortened by disulfiram. Large interindividual variations occurred; one volunteer with a very short initial plasma antipyrine half-life shortened, rather than prolonged, his antipyrine half-life after 10 days of disulfiram. In the first 10-day study the apparent volume of distribution of antipyrine was significantly increased in each volunteer after disulfiram administration, whereas in the second 10-day study, disulfiram failed to alter this value. Another anomalous result concerned attempts to determine whether a correlation existed between the initial antipyrine half-life and the percent change in this value produced by disulfiram administration. A significant correlation occurred in the initial 10-day study (r = 0.71, p < 0.05), whereas neither in the second 10-day study (r = 0.20, p > 0.05) nor in the 4-day study (r = 0.57, p > 0.05) was a significant correlation observed. Each of the three studies revealed no significant correlation between the initial metabolic clearance rate of antipyrine and the percent change in this value produced by disulfiram administration.