![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 31, Issue 3, 343-343, March 2003
 |
Letter |
|---|
 Top
 Letter
 References
|
|---|
Chemical inhibitors
that are selective for specific human cytochrome P450
(P4501) enzymes are essential tools in the
determination of the contribution of these enzymes in the metabolism of
new chemical entities (Ring and Wrighton, 2000
). While potent, specific
inhibitors are available for many of the human P450 enzymes (e.g.,
quinidine for CYP2D6, furafylline for CYP1A2, etc.), such a compound
has not been available for CYP2C19. S-Mephenytoin has been
used as an inhibitor for CYP2C19, however this compound is a substrate
for this enzyme, and high concentrations are required for its use as an
inhibitor (Yoshimoto et al., 1995; Mankowski, 1999). Omeprazole has
been used as a CYP2C19 inhibitor, but it also inhibits CYP2C9 (Ko et
al., 1997). Ticlopidine has also been recently used as an inhibitor of
CYP2C19, however this compound is not selective for this enzyme as it
also is a potent inhibitor of CYP2D6 (Mankowski, 1999; Ko et al.,
2000). Although these agents can be used for inhibition of CYP2C19,
they are not optimal.
In a recent report in this journal, the synthesis and testing of
N-3-benzylnirvanol and N-3-benzylphenobarbital
enantiomers as inhibitors of human cytochrome P450 enzymes were
described (Suzuki et al., 2002). (+)N-3-Benzylnirvanol was
shown to be a potent inhibitor of CYP2C19 catalyzed
S-mephenytoin 4'-hydroxylase activity in human liver
microsomes with a Ki value of 0.25 µM, while not appreciably inhibiting CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, and 3A4 activities. Thus, (+)N-3-benzylnirvanol appeared to
be a promising tool for selective inhibition of CYP2C19.
However, the potential for (+)N-benzylnirvanol to inhibit
human CYP2B6 was not tested in the aforementioned report. Since N-benzylnirvanol is an analog of nirvanol, the metabolite
arising from CYP2B6 catalyzed mephenytoin metabolism (Heyn et al.,
1996; Ekins et al., 1998), we had concerns that this promising new
inhibitor may lack true selectivity for CYP2C19 and cause appreciable
inhibition of CYP2B6. To this end, we prepared
(+)N-benzylnirvanol according to the described procedure
(Suzuki et al., 2002), and tested it as an inhibitor of
CYP2B6-catalyzed bupropion hydroxylase activity, a marker activity for
this P450 enzyme (Faucette et al., 2000; Hesse et al., 2000), as well
as other human P450 enzymes using standard enzyme-specific marker activities.
We confirmed the results reported by Suzuki et al. (2002).
(+)N-Benzylnirvanol potently inhibited CYP2C19 activity
(IC50 = 0.41 µM) and did not inhibit CYP1A2,
2A6, 2C9, 2D6, and 3A activities in human liver microsomes at
concentrations of up to 30 µM. (+)N-Benzylnirvanol mildly
inhibited CYP2B6 (IC50 = 58 µM), yielding an
approximate 140X selectivity between CYP2C19 and CYP2B6. Our conclusion
is that (+)N-benzylnirvanol possesses appropriate potency
and selectivity as an inhibitor for CYP2C19 and should be the agent of
choice when determining whether CYP2C19 is involved in the metabolism of a new drug or chemical.
| |
Footnotes |
|---|
Received November 19, 2002; accepted November 20, 2002.
Address correspondence to: R. Scott Obach, MS 4088, Pfizer Global Research and Development, Groton, CT 06340. E-mail: obachrs{at}groton.pfizer.com
| |
Abbreviations |
|---|
Abbreviations used are: P450, cytochrome P450.
| |
References |
|---|
|
Top
Letter
References
|
|---|
) bufuralol, the prototypic substrate of CYP2D6.
Drug Metab Dispos
27:
1024-1028)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19.
Drug Metab Dispos
30:
235-239This article has been cited by other articles:
|
|
 |
|
  C. Lu, C. Berg, S. R. Prakash, F. W. Lee, and S. K. Balani Prediction of Pharmacokinetic Drug-Drug Interactions Using Human Hepatocyte Suspension in Plasma and Cytochrome P450 Phenotypic Data. III. In Vitro-in Vivo Correlation with Fluconazole Drug Metab. Dispos., July 1, 2008; 36(7): 1261 - 1266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lu, G. T. Miwa, S. R. Prakash, L.-S. Gan, and S. K. Balani A Novel Model for the Prediction of Drug-Drug Interactions in Humans Based on in Vitro Cytochrome P450 Phenotypic Data Drug Metab. Dispos., January 1, 2007; 35(1): 79 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cai, R. W. Wang, R. W. Edom, D. C. Evans, M. Shou, A. D. Rodrigues, W. Liu, D. C. Dean, and T. A. Baillie VALIDATION OF (-)-N-3-BENZYL-PHENOBARBITAL AS A SELECTIVE INHIBITOR OF CYP2C19 IN HUMAN LIVER MICROSOMES Drug Metab. Dispos., June 1, 2004; 32(6): 584 - 586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Walsky and R. S. Obach VALIDATED ASSAYS FOR HUMAN CYTOCHROME P450 ACTIVITIES Drug Metab. Dispos., June 1, 2004; 32(6): 647 - 660. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
