Quantitative in vitro phenotyping and prediction of drug interaction potential of CYP2B6 substrates as victims

Abstract

1. Determination of f_{m, CYP} for a compound is critical to assess the potential risk of a drug candidate as a victim of DDI. Several compounds are identified as CYP2B6 substrates, but the f_{m, CYP2B6} values are not determined quantitatively.

2. Two methods of reaction phenotyping, the chemical inhibition method and metabolism in rCYP enzymes, were used to determine the relative contributions of the enzymes. Chemical inhibition method was also conducted in the presence of BSA (0.5% w/v).

3. The results confirm with the earlier studies concerning the identity of the CYP2B6 enzyme. The f_{m, CYP2B6} values for artemisinin, bupropion, clopidogrel, ketamine, selegiline, sertraline and ticlopidine were 0.24, 0.28, 0.15, 0.45, 0.46, 0.42 and 0.54, respectively, in HLM determined by chemical inhibition method. The f_{m, CYP2B6} values for artemisinin, bupropion, clopidogrel, ketamine, selegiline, sertraline and ticlopidine were 0.46, 0.17, 0.15, 0.60, 0.51, 0.66 and 0.77, respectively, in HLM determined by chemical inhibition method in the presence of BSA (0.5% w/v).

4. Bupropion metabolism is majorly mediated by CYP2C19 (0.41) with a minor contribution from CYP2B6 (0.16) in the presence of BSA. Ticlopidine is a time-dependent inhibitor of both CYP2B6 and CYP2C19 that can inhibit the bupropion metabolism by 50–60%.

• Chemical inhibition
• DDI
• f_{m CYP2B6}
• HLM
• ISEF
• mechanistic static model
• rCYP
• RAF
• victim

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of this manuscript.

Supplementary material available online