QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: dmd.108.023655v1 37/3/644    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Talakad, J. C. Articles by Halpert, J. R. Search for Related Content PubMed PubMed Citation Articles by Talakad, J. C. Articles by Halpert, J. R.

Decreased Susceptibility of the Cytochrome P450 2B6 Variant K262R to Inhibition by Several Clinically Important Drugs

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California

Cytochrome P450 (P450) 2B6 metabolizes a number of clinically relevant drugs and is one of the most highly polymorphic human P450 enzymes, with the Lys²⁶²Arg substitution being especially common in several genetic variants. Therefore, K262R (2B6*4) was created in the CYP2B6dH background (N-terminal-modified and C-terminal His-tagged) and expressed in Escherichia coli. The recombinant CYP2B6dH and K262R were purified and studied to investigate the effect of the Lys²⁶²Arg substitution with six of the most potent drug inhibitors of CYP2B6, namely, clopidogrel, clotrimazole, itraconazole, raloxifene, sertraline, and ticlopidine. K262R showed a >3-fold increase in the K_i values with clopidogrel, itraconazole, and raloxifene and 6-fold increase in K_i with sertraline compared with CYP2B6dH. Likewise, K262R showed 2-, 4-, and >20-fold higher K_s values than CYP2B6dH with clopidogrel, sertraline, and itraconazole, respectively. In contrast, when tested with several known type II inhibitors of CYP2B enzymes, K262R showed a 10-fold lower IC₅₀ with 4-(phenyl)pyridine and 2-fold lower IC₅₀ with 4-(4-nitrobenzyl)pyridine or 1-(4-phenyl)benzylimidazole than CYP2B6dH. Subsequent analysis predicted possible in vivo drug-drug interactions between the CYP2B6 substrate efavirenz and drug inhibitors clopidogrel, clotrimazole, itraconazole, sertraline, and ticlopidine. Furthermore, Q172H/K262R (2B6*6), which is the most common genetic variant of CYP2B6 harboring K262R, was created in CYP2B6dH, expressed, purified, and characterized for inhibition. Q172H/K262R showed a >6-fold increase in K_i with sertraline and clopidogrel compared with CYP2B6dH. The results suggest that individuals, especially homozygotes, with the 2B6*4 or 2B6*6 allele might be less susceptible to drug interactions resulting from P450 inhibition.

This article has been cited by other articles:

				A. J. Lau and T. K. H. Chang Inhibition of Human CYP2B6-Catalyzed Bupropion Hydroxylation by Ginkgo biloba Extract: Effect of Terpene Trilactones and Flavonols Drug Metab. Dispos., September 1, 2009; 37(9): 1931 - 1937. [Abstract] [Full Text] [PDF]