Prediction of Clearance Changes of Drugs that are Substrates of Major Cytochrome P450 Enzymes Caused by Drug-Drug Interaction or Single Nucleotide Polymorphism

[Background] Drug-drug interactions (DDIs) caused by inhibition of drug metabolizing enzymes are very important in clinical situations.  Regarding the DDIs caused by inhibition of cytochrome P450 (CYP) 3A4, we previously established the CR-IR method to quantitatively and comprehensively predict magnitude of DDIs after oral administration based on the ratio of the contribution of CYP3A4 to clearance after oral absorption (CR_CYP3A4) and the time-averaged apparent inhibition ratio of CYP3A4 (IR_CYP3A4)^1,2).  The CR-IR method has been extended to predict DDIs which are associated with induction of CYP3A4³⁾.  However, prediction of the magnitude of DDIs caused by inhibition of other important CYP enzymes, such as CYP1A2, CYP2C9, CYP2C19 and CYP2D6, remained to be established.  [Objective] The objective of the present study is to examine whether the CR-IR method is applicable to these four CYP enzymes.  In addition, we also tried to clarify whether it is applicable to single nucleotide polymorphisms (SNPs) in CYP enzymes in the same manner.  [Data sources] The analysis was based on 382 DDI studies reported in 246 published articles over a period 1975~2009.  In addition, 12 articles published over a period 1995 - 2008, in which increase in the AUC of substrate drugs in SNPs carriers of CYP2D6*10 is reported, were analyzed.  [Methods] The increase in the AUC of substrate drugs by co-administration of an inhibitor drug was calculated by 1 / (1 – CR-IR).  By using the reduction ratio (RR), which represents the ratio for the reduction in metabolizing activity of SNPs type enzyme to that of the wild type enzyme, the increase in the AUC of substrate drugs in SNPs carriers compared to that in the wild type subjects is given by 1 / (1 – CR-RR).  Regarding the DDIs, we determined CR values of 22, 11, 4 and 6 substrate drugs and IR values of 18, 11, 7 and 3 inhibitor drugs for CYP2D6, CYP2C9, CYP1A2 and CYP2C19, respectively.  Besides, CR and IR values of 24 substrate and 5 inhibitor drugs for CYP3A4 were added to those reported previously¹⁾.  [Results] The increases in the AUC of substrate drugs of various CYP enzymes associated with inhibition or SNPs were successfully predicted within 50~200% of the observed values for 375 studies (98.2%).  In addition, from RR obtained in the analysis, it was found that the enzyme activity of CYP2D6*10 homozygotes, which is observed very frequently in Asians, accounts for 23% compared with that of the wild type CYP2D6. [Conclusion] The CR-IR method to predict increase in the AUC of substrate drugs caused by DDIs and those observed in SNPs carriers has wide applicability.  It may be useful to raise alerts appropriately to enable adjusting dose or replacing regimes in DDI situations of various CYP enzymes as has been demonstrated for CYP3A4⁴⁾.  Reference: ¹⁾ Ohno et al., Clin Pharmacokinet. 2007; 46: 681-96. ²⁾ Hisaka et al., Pharmacol. Ther. 2010; 125: 230-48. ³⁾ Ohno et al., Clin Pharmacokinet. 2008; 47: 669-80.  ⁴⁾ Hisaka et al., Clin Pharmacokinet, 2009: 48: 653-66.