A Forum for Improving Drug Safety

Drug Metab Dispos. 2008 Dec 12
Talakad JC, Kumar S, Halpert JR. University of California San Diego.

Cytochrome P450 (CYP) 2B6 metabolizes a number of clinically relevant drugs and is one of the most highly polymorphic human P450 enzymes, with the Lys(262)–>Arg 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 E. coli. The recombinant CYP2B6dH and K262R were purified and studied to investigate the effect of the Lys(262)– >Arg 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 Ki values with clopidogrel, itraconazole, and raloxifene and ~ 6-fold increase in Ki with sertraline, compared with CYP2B6dH. Similarly, K262R showed 2-, 4-, and > 20-fold higher Ks 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 Ki 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.

PMID: 19074527

Filed under: Cytochrome P450, Personalized Medicine, Pharmacogenetics Tagged: | Cytochrome, Cytochrome P450, cytochromes, Personalized Medicine, Pharmacogenetics