TY - JOUR T1 - Confirmation That Cytochrome P450 2C8 (CYP2C8) Plays a Minor Role in (<em>S</em>)-(+)- and (<em>R</em>)-(-)-Ibuprofen Hydroxylation in Vitro JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2513 LP - 2522 DO - 10.1124/dmd.108.022970 VL - 36 IS - 12 AU - Shu-Ying Chang AU - Wenying Li AU - Sarah C. Traeger AU - Bei Wang AU - Donghui Cui AU - Hongjian Zhang AU - Bo Wen AU - A. David Rodrigues Y1 - 2008/12/01 UR - http://dmd.aspetjournals.org/content/36/12/2513.abstract N2 - Various groups have sought to determine the impact of CYP2C8 genotype (and CYP2C8 inhibition) on the pharmacokinetics (PK) of ibuprofen (IBU) enantiomers. However, the contribution of cytochrome P450 2C8 (CYP2C8) in human liver microsomes (HLMs) has not been reported. Therefore, in vitro cytochrome P450 (P450) reaction phenotyping was conducted with selective inhibitors of cytochrome P450 2C9 (CYP2C9) and CYP2C8. In the presence of HLMs, sulfaphenazole (CYP2C9 inhibitor), and anti-CYP2C9 monoclonal antibodies (mAbs) inhibited (73–100%) the 2- and 3-hydroxylation of both IBU enantiomers (1 and 20 μM). At a higher IBU concentration (500 μM), the same inhibitors were less able to inhibit the 2-hydroxylation of (S)-(+)-IBU (32–52%) and (R)-(-)-IBU (30–64%), whereas the 3-hydroxylation of (S)-(+)-IBU and (R)-(-)-IBU was inhibited 66 to 83 and 70 to 89%, respectively. In contrast, less inhibition was observed with montelukast (CYP2C8 inhibitor, ≤35%) and anti-CYP2C8 mAbs (≤24%) at all concentrations of IBU. When (S)-(+)-IBU and (R)-(-)-IBU (1 μM) were incubated with a panel of recombinant human P450s, only CYP2C9 formed appreciable amounts of the hydroxy metabolites. At a higher IBU enantiomer concentration (500 μM), additional P450s catalyzed 2-hydroxylation (CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP2B6) and 3-hydroxylation (CYP2C19). When the P450 reaction phenotype and additional clearance pathways are considered (e.g., direct glucuronidation and chiral inversion), it is concluded that CYP2C8 plays a minor role in (R)-(-)-IBU (&lt;10%) and (S)-(+)-IBU (∼13%) clearance. By extension, one would not expect CYP2C8 inhibition (and genotype) to greatly affect the pharmacokinetic profile of either enantiomer. On the other hand, CYP2C9 inhibition and genotype are expected to have an impact on the PK of (S)-(+)-IBU. The American Society for Pharmacology and Experimental Therapeutics ER -