Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity

Tung Yuan Shih, Shan Chu Ho, Cheng Huei Hsiong, Tien Yu Huang, Oliver Yoa Pu Hu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background &Aims: 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.

Original languageEnglish
Pages (from-to)720-728
Number of pages9
JournalCurrent Drug Metabolism
Volume14
Issue number6
DOIs
Publication statusPublished - Jul 1 2013
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP2E1
Excipients
Isoniazid
Rifampin
Mannitol
Pharmaceutical Preparations
Liver
United States Food and Drug Administration
Aspartate Aminotransferases
Malondialdehyde
Alanine Transaminase
Galactose
Assays
Chlorzoxazone
Liver Function Tests
Enzyme activity
Glutathione
Animals

Keywords

  • GSP method
  • Hepatotoxicity
  • Isoniazid
  • Mannitol
  • Rifampicin
  • Tuberculosis

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry

Cite this

Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity. / Shih, Tung Yuan; Ho, Shan Chu; Hsiong, Cheng Huei; Huang, Tien Yu; Hu, Oliver Yoa Pu.

In: Current Drug Metabolism, Vol. 14, No. 6, 01.07.2013, p. 720-728.

Research output: Contribution to journalArticle

Shih, Tung Yuan ; Ho, Shan Chu ; Hsiong, Cheng Huei ; Huang, Tien Yu ; Hu, Oliver Yoa Pu. / Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity. In: Current Drug Metabolism. 2013 ; Vol. 14, No. 6. pp. 720-728.
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AU - Shih, Tung Yuan

AU - Ho, Shan Chu

AU - Hsiong, Cheng Huei

AU - Huang, Tien Yu

AU - Hu, Oliver Yoa Pu

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Background &Aims: 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.

AB - Background &Aims: 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.

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KW - Isoniazid

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KW - Rifampicin

KW - Tuberculosis

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