The Role of the Gut Flora in the Metabolism of Prontosil and Neoprontosil in the Rat

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Abstract
1. The urinary excretion of total sulphanilamide (free and acetylated) in rats receiving Prontosil or Neoprontosil orally is considerably reduced when the rats are treated with antibiotics to suppress their intestinal flora. The absorption and metabolism of sulphanilamide are unaffected by such treatment with antibiotics. 2. The lipid-soluble Prontosil after oral or intraperitoneal administration is partly excreted in the bile as a polar conjugate, apparently an N-glucuronide, and this drug appears to be converted into sulphanilamide partly by metabolism by the body tissues and partly by enterofloral metabolism. 3. The polar, water-soluble Neoprontosil is poorly absorbed from the intestine and when given orally is largely reduced to sulphanilamide by the gut flora before absorption. When given intraperitoneally, a large proportion (up to 70%) of the drug is excreted in the bile unchanged, and it would appear that only a small proportion of the drug (ca. 20%) is converted to sulphanilamide in the tissues, the major conversion occurring in the intestine after biliary excretion. 4. The reduction of Neoprontosil by the tissues is stimulated by pretreatment of the animals with phenobarbitone, but its reduction by the gut flora is unaffected by phenobarbitone pretreatment. 5. The conversion of Prontosil and Neoprontosil to sulphanilamide in the rat is an example of drug activation by the intestinal flora.