Regional gastrointestinal permeability of rifampicin and isoniazid (alone and their combination) in the rat.
OBJECTIVE
To determine if rifampicin (RMP) and isoniazid (INH) are absorbed from different gastrointestinal tract (GIT) sites, and to ascertain the feasibility of producing new fixed-dose combination (FDC) products containing RMP and INH by segregating drug delivery at different sites along the GIT.


METHODS
Permeability of RMP and INH (alone and in combination) was determined in various segments of rat GIT (stomach, duodenum, jejunum and ileum) at concentrations of respectively 2.4 and 1.2 mg/ml, using a ligated loop technique. Drug analysis was performed by HPLC. Extent of absorption was considered as the total drug disappearing from the loop. Permeability was correlated with solubility and decomposition data at pH corresponding to different GIT sites.


RESULTS
RMP was well absorbed from the stomach due to its solubility, which was maximum between pH 1-2. INH was poorly absorbed from the stomach, but was well absorbed from all three segments of the intestine. In combination, RMP disappearance was enhanced in the presence of INH in the stomach and jejunum, but INH disappearance was not influenced by RMP.


CONCLUSIONS
The study shows higher in situ RMP disappearance in the presence of INH, attributable to drug degradation due to catalysis by INH. As the two drugs show regional specific permeability, FDCs without reduced RMP bioavailability resulting from its decomposition in the presence of INH can be designed by segregating delivery of the two drugs by around 3-4 h. RMP should be released in the stomach and INH in the intestine.
Mariappan
T T
TT
Department of Pharmaceutical Analysis, NIPER, SAS Nagar, India.
Singh
S
S
D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004064:Digestive System / Q000378:metabolism*; D004338:Drug Combinations; D005753:Gastric Mucosa / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000995:Antitubercular Agents; D004338:Drug Combinations; D007538:Isoniazid; D012293:Rifampin