Abstract
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 (<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.
Footnotes
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.108.022970.
-
ABBREVIATIONS: ADME, absorption-distribution-metabolism-excretion; IBU, 2-(4-isobutylphenyl)propionic acid, ibuprofen; P450, cytochrome P450; rCYP2C8, recombinant cytochrome P450 2C8; rCYP2C9, recombinant cytochrome P450 2C9; PK, pharmacokinetics; mAb, monoclonal antibody; HLM, human liver microsomes; 2-OH, 2-hydroxyibuprofen; 3-carboxy-IBU, 3-(4-(1-carboxyethyl)phenyl)-2-methylpropanoic acid, 3-carboxyibuprofen; 3-OH, 2-(4-(3-hydroxy-2-methylpropyl)phenyl)-propanoic acid, 3-hydroxyibuprofen; HPLC, high-performance liquid chromatography; NR, normalized rate; TNR, total normalized rate; LC-MS/MS, liquid chromatography-tandem mass spectrometry; CLint, intrinsic clearance (Vmax/Km); OATP, organic anion-transporting peptide; AUC, area under the plasma concentration versus time curve.
- Received June 24, 2008.
- Accepted September 10, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|