Evidence of efflux-mediated and saturable absorption of rifampicin in rat intestine using the ligated loop and everted gut sac techniques.
This study was carried out to explore whether efflux-mediated and saturable mechanisms play any role toward poor and variable intestinal absorption of rifampicin. In situ segmental permeability of rifampicin at various residence times was determined in rat gastrointestinal tract using the ligated loop technique. The involvement of efflux-mediated and saturable absorption of rifampicin was studied in rat intestine using the everted sac method. The samples were analyzed by a validated HPLC method. Rifampicin showed decreased permeability in jejunum and ileum with an increase in residence time. The permeation of rifampicin from the serosal to the mucosal side (secretion) was significantly higher than permeation from the mucosal to the serosal side (absorption) of jejunum and ileum. This indicated the involvement of efflux-mediated transport. Addition of verapamil, an inhibitor for P-glycoprotein (Pgp), multidrug resistance associated protein-2 (MRP-2), and other related transporters, increased absorption of rifampicin in jejunum and ileum by 2-3-fold and decreased secretion by almost 4-fold. The permeation rate (flux) of rifampicin through duodenum increased with concentration up to 300 microg/mL, becoming constant thereafter, indicating the existence of saturable absorption. There was no saturable permeation in jejunum and ileum. Thus the present study indicates the involvement of efflux-mediated and saturable absorption mechanisms of rifampicin in rat intestine, which act as barriers to the absorption of the drug. This explains the drug's poor absolute bioavailability. As Pgp varies from person to person to an extent of 2-8-fold, it can be one direct reason for the interindividual variable bioavailability shown by rifampicin.
Mariappan
T T
TT
Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar 160 062, India.
Singh
Saranjit
S
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D013505:Digestive System Surgical Procedures; D004305:Dose-Response Relationship, Drug; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000601:surgery; D008026:Ligation; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors; D023421:Models, Animal; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D012293:Rifampin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology
D000904:Antibiotics, Antitubercular; D002121:Calcium Channel Blockers; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012293:Rifampin; D014700:Verapamil