Role of the gut flora in the reduction of sulphoxide containing drugs

Strong, H. Andrew (1985) Role of the gut flora in the reduction of sulphoxide containing drugs. University of Southampton, Doctoral Thesis.

Abstract

The antiplatelet effects of sulphinpyrazone (SO) may be due to its thioether/sulphide (S) metabolite. These studies have examined the pharmacokinetics of SO and S in rabbits and humans to define the site of, and factors that may influence, S production. In rabbits, comparison of oral and IV administration of SO showed that the oral route was associated with an incomplete bioavailability (35% ) and a 6-fold greater formation of S. Studies in vitro showed that the contents of the caecum had the greatest capacity to reduce SO while the liver had slight activity under anaerobic but not under aerobic conditions. In 11 normal volunteers there was a 20-fold variation in S formation assessed from the area under the plasma concentration-time curves (AUC) with only a 3-fold variation in the AUC of SO. Much of the variation in S formation may be due to individual differences in the number and/or activity of active bacteria (in vitro studies demonstrated a 5-fold variation in human faecal So reducing activity) and intestinal transit times. There was an inverse correlation (p< 0.01) between the intestinal transit time of SO and the AUC of S. Reducing the intestinal transit time by the coadministration of metoclopramide to 4 volunteers resulted in a 5-fold (p< 0.05) increase in AUC of S. The definitive evidence to implicate the gut flora of man in SO reduction was gained by showing that patients without large intestines (ileostomy patients) were unable to form S. This success prompted a further study using ileostomy patients to define the role of the gut flora in the reduction of sulindac to its active sulphide metabolite. The results suggested that 50% of sulindac sulphide is formed by the gut flora and highlighted the potential of this virtually unexploited model for defining the role of the gut flora in drug metabolism in man. Incubation of SO and sulidac with pure cultures of bacteria showed that sulindac was reduced by both aerobes and anaerobes while SO reduction was negligible in anaerobes and slower than sulindac in aerobes. However, in vivo studies examining the effects of antibiotics indicated that anaerobes may be most important in SO reduction. The possible role of the gut flora in the metabolism of other sulphoxide containing drugs is discussed. (D68672/86)

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