title: Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity.
abstract: OBJECTIVE
  The incidence of isoniazid (INH)- and rifampicin (RIF)-induced abnormal liver enzyme activity is 27% but only 19% with INH alone. Cytochrome P450 2E1 (CYP2E1) is thought to contribute to the synergistic effects of RIF and INH. Pharmaceutical excipients are inactive ingredients that are added to a pharmaceutical compound. The purpose of this study was to screen excipients for CYP2E1 inhibition and identify whether the screened excipients prevented INH/RIF-induced hepatotoxicity.
  
  
  METHODS
  Fifty-five known pharmaceutical excipients were screened for CYP2E1 inhibition. The hepatotoxic doses of INH and RIF were 50 and 100 mg/kg/day, respectively. Hepatotoxicity was assessed by the galactose single point (GSP) method (a US Food and Drug Administration (FDA) recommended quantitative liver function test), liver histopathology, malondialdehyde (MDA) assay, and measurement of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. We chose the CYP2E1-specific substrate chlorzoxazone to assess CYP2E1 activity in animal and human.
  
  
  RESULTS
  Mannitol inhibited CYP2E1 activity by 54% in mice with INH/RIF-induced hepatotoxicity (p < 0.005). Serum AST, ALT and GSP levels were significantly increased 3.8- to 7.8-fold in these mice (p < 0.005), and these levels could be lowered by mannitol. Mannitol significantly alleviated the depletion of hepatic glutathione (GSH) and partially reversed the increase in MDA formation in mice treated with INH/RIF (p < 0.005). Mannitol also decreased CYP2E1 activity by 58% in humans (p < 0.005). Furthermore, an antituberculosis (TB) efficacy assay revealed that mannitol did not affect the anti-TB effects of INH/RIF.
  
  
  CONCLUSIONS
  Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugs that induce hepatotoxicity through CYP2E1, such as INH and RIF.
authors.affiliation: School of Pharmacy of National Defense Medical Center, P.O. Box 90048-512, Taipei, Taiwan, ROC.
authors.forename: Tung-Yuan
authors.initials: TY
authors.lastname: Shih
authors.forename: Shan-Chu
authors.initials: SC
authors.lastname: Ho
authors.forename: Cheng-Huei
authors.initials: CH
authors.lastname: Hsiong
authors.forename: Tien-Yu
authors.initials: TY
authors.lastname: Huang
authors.forename: Oliver Yoa-Pu
authors.initials: OY
authors.lastname: Hu
mesh_terms: D000328:Adult; D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004338:Drug Combinations; D005079:Excipients / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008353:Mannitol / Q000008:administration & dosage*; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004338:Drug Combinations; D005079:Excipients; D008353:Mannitol; D007538:Isoniazid; D012293:Rifampin