Association of cyp2c9*2 with bosentan-induced liver injury

S. M. Markova; T. De Marco; N. Bendjilali; E. A. Kobashigawa; J. Mefford; J. Sodhi; H. Le; C. Zhang; J. Halladay; A. E. Rettie; C. Khojasteh; D. McGlothlin; A. H.B. Wu; W. C. Hsueh; J. S. Witte; J. B. Schwartz; D. L. Kroetz

doi:10.1038/clpt.2013.143

Association of cyp2c9*2 with bosentan-induced liver injury

S. M. Markova, T. De Marco, N. Bendjilali, E. A. Kobashigawa, J. Mefford, J. Sodhi, H. Le, C. Zhang, J. Halladay, A. E. Rettie, C. Khojasteh, D. McGlothlin, A. H.B. Wu, W. C. Hsueh, J. S. Witte, J. B. Schwartz, D. L. Kroetz

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Abstract

Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

Original language	English (US)
Pages (from-to)	678-686
Number of pages	9
Journal	Clinical Pharmacology and Therapeutics
Volume	94
Issue number	6
DOIs	https://doi.org/10.1038/clpt.2013.143
State	Published - Dec 2013
Externally published	Yes

All Science Journal Classification (ASJC) codes

Pharmacology
Pharmacology (medical)

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Markova, S. M., De Marco, T., Bendjilali, N., Kobashigawa, E. A., Mefford, J., Sodhi, J., Le, H., Zhang, C., Halladay, J., Rettie, A. E., Khojasteh, C., McGlothlin, D., Wu, A. H. B., Hsueh, W. C., Witte, J. S., Schwartz, J. B., & Kroetz, D. L. (2013). Association of cyp2c9*2 with bosentan-induced liver injury. Clinical Pharmacology and Therapeutics, 94(6), 678-686. https://doi.org/10.1038/clpt.2013.143

@article{8b320de6df1a4301b6170e27a7fb0a9b,

title = "Association of cyp2c9*2 with bosentan-induced liver injury",

abstract = "Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.",

author = "Markova, {S. M.} and {De Marco}, T. and N. Bendjilali and Kobashigawa, {E. A.} and J. Mefford and J. Sodhi and H. Le and C. Zhang and J. Halladay and Rettie, {A. E.} and C. Khojasteh and D. McGlothlin and Wu, {A. H.B.} and Hsueh, {W. C.} and Witte, {J. S.} and Schwartz, {J. B.} and Kroetz, {D. L.}",

year = "2013",

month = dec,

doi = "10.1038/clpt.2013.143",

language = "English (US)",

volume = "94",

pages = "678--686",

journal = "Clinical Pharmacology and Therapeutics",

issn = "0009-9236",

publisher = "Nature Publishing Group",

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Markova, SM, De Marco, T, Bendjilali, N, Kobashigawa, EA, Mefford, J, Sodhi, J, Le, H, Zhang, C, Halladay, J, Rettie, AE, Khojasteh, C, McGlothlin, D, Wu, AHB, Hsueh, WC, Witte, JS, Schwartz, JB & Kroetz, DL 2013, 'Association of cyp2c9*2 with bosentan-induced liver injury', Clinical Pharmacology and Therapeutics, vol. 94, no. 6, pp. 678-686. https://doi.org/10.1038/clpt.2013.143

TY - JOUR

T1 - Association of cyp2c9*2 with bosentan-induced liver injury

AU - Markova, S. M.

AU - De Marco, T.

AU - Bendjilali, N.

AU - Kobashigawa, E. A.

AU - Mefford, J.

AU - Sodhi, J.

AU - Le, H.

AU - Zhang, C.

AU - Halladay, J.

AU - Rettie, A. E.

AU - Khojasteh, C.

AU - McGlothlin, D.

AU - Wu, A. H.B.

AU - Hsueh, W. C.

AU - Witte, J. S.

AU - Schwartz, J. B.

AU - Kroetz, D. L.

PY - 2013/12

Y1 - 2013/12

N2 - Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

AB - Bosentan (Tracleer) is an endothelin receptor antagonist prescribed for the treatment of pulmonary arterial hypertension (PAH). Its use is limited by drug-induced liver injury (DILI). To identify genetic markers of DILI, association analyses were performed on 56 Caucasian PAH patients receiving bosentan. Twelve functional polymorphisms in five genes (ABCB11, ABCC2, CYP2C9, SLCO1B1, and SLCO1B3) implicated in bosentan pharmacokinetics were tested for associations with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and DILI. After adjusting for body mass index, CYP2C9*2 was the only polymorphism associated with ALT, AST, and DILI (β = 2.16, P = 0.024; β = 1.92, P = 0.016; odds ratio 95% CI = 2.29-∞, P = 0.003, respectively). Bosentan metabolism by CYP2C9*2 in vitro was significantly reduced compared with CYP2C9*1 and was comparable to that by CYP2C9*3. These results suggest that CYP2C9*2 is a potential genetic marker for prediction of bosentan-induced liver injury and warrants investigation for the optimization of bosentan treatment.

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U2 - 10.1038/clpt.2013.143

DO - 10.1038/clpt.2013.143

M3 - Article

C2 - 23863877

AN - SCOPUS:84887988640

SN - 0009-9236

VL - 94

SP - 678

EP - 686

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

IS - 6

ER -

Association of cyp2c9*2 with bosentan-induced liver injury

Abstract

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