The apparently contradictory views expressed by me and Dutta regarding the se- rum level of furazolidone in reply to the letter from Goyal(1) are sure to confuse many and need clarification.

The very fact that the urine becomes in- tensely colored following oral furazolidone is enough to establish that there is absorption taking place. Using 14C labeled oral dose, investigators were able to demonstrate significant radioactivity in the urine of animals. Earlier measurements of the drug level overestimated furazolidone levels in urine as the method was not specific for intact furazolidone in the presence of it's metabolites that are convertible to 5-nitrofurfural phenylhydrazine(2). All these led to the belief that furazolidone was being absorbed as such. The method described by Hollifield and Conklin is specific for the intact drug even in the presence of its metabolites. When this method was employed; no intact drug was detected in animal or human urine even though the . method is sensitive at least above 2 µg/ml. High pressure liquid chromatography, again sensitive and specific for the intact drug found furazolidone levels to be less than 1 µg/ml in the serum(2). Thus it has become clear that the serum contains only negligible amounts of furazolidone and the abundant compounds detected earlier by 14C and other experiments were its metabolites. Experimentally it has been shown that furazolidone degrades rapidly when incubated with tissues like the intestine, muscle, kidney, liver,. etc. (but not the blood)(2,3). The rate of degradation can be as high as 100 mg/kg of tissue/hour(3). Hence it is likely that furazolidone is broken down in the intestine itself and what is absorbed is the metabolites of furazolidone rather than intact furazolidone. It is also probable that furazolidone gets degraded' in other tissues as well.

Now the pertinent question is whether these metabolites themselves are active compounds. The best way to look at it is to incubate Salmonella typhi organisms with the serum of children on treatment with furazolidone and see whether its growth is inhibited so that the combined effect of furazolidone and it's metabolites present in serum can be assessed. Studies of this nature have found that serum bactericidal activity of children on furazolidone treatment is not high enough for consistent clinical efficacy(4). Thus whatever metabolites that are present in the serum are inactive for clinical purposes. That is why furazolidone is cosidered as a non-absorbable drug for clinical purposes though a more matter of fact statement would be that "furazolidone achieves poor serum levels" as I have stated in my communication(1).

The next question is whether the small amount of intact furazolidone available in the serum is enough to tackle the Salmonella typhi in the blood. That it is insufficient for this purpose has already been shown(4,5). E. coli, Staphylococci etc. are sensitive in vitro to furazolidone(2,3). In fact the minimum inhibitory concentration of furazolidone required for E. coli is less than that required for Salmonella typhi(3). Yet nobody has ever successfully treated a systemic E. coli or Staphylococcal infection with furazolidone. Hence logically it does not stand to reason to believe that in typhoid fever, systemic action of furazolidone is primarily responsible for a cure. That is why intestine is considered as the primary site of action of furazolidone in typhoid fever. The probable mechanism by which typhoid fever can be cured just by the local action of furazolidone in the intestine has already been postulated(4).

I have suggested in earlier communications that furazolidone can be effective in treating typhoid fever in the immuno competent host(4). However, one cannot rely too much on the immune competence of a sick child. That may be the reason why the reputed textbooks of pediatrics do not mention furazolidone as a standard treatment modality.

I hope that this communication may help to settle the doubts regarding the serum level of furazolidone.

A. Santhosh Kumar,
Assistant Professor,
Department of Pediatrics,
Medical College (SAT) Hospital,
Thiruvananthapuram 695 011,
India.