CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype

Variation in drug disposition and response is associated with many anticancer agents, in part due to large inter-patient differences in pharmacokinetics (Petros and Evans, 2004). This may be the result of variable expression of hepatic cytochrome P450 (CYP), enzymes which play an important role in the metabolism and elimination of many chemotherapeutic drugs. CYP2C19 is an important member of the CYP family of enzymes and is involved in the metabolism of a diverse range of drug substrates such as the antiulcer agent omeprazole (OMP) (Desta et al, 2002) and the antimalarial drug proguanil (Ward et al, 1991). Recently, it has become apparent that CYP2C19 is also important in the disposition of a number of chemotherapeutic agents, including cyclophosphamide (Takada et al, 2004; Timm et al, 2005), thalidomide (Ando et al, 2002; Li et al, 2007) and bortezomib (Uttamsingh et al, 2005). There is a loss of function genetic polymorphism associated with the CYP2C19 enzyme, with the result that individuals who are homozygous variant (var/var) are ‘poor metabolisers' (PM) of drugs that are substrates for CYP2C19 (Desta et al, 2002). Approximately 3% of Caucasians and up to 30% of Asians are CYP2C19 PM (Xie et al, 1999). Numerous studies have shown a correlation between variant genotype and PM phenotype in healthy populations (Xie et al, 1999; Desta et al, 2002). Hence, the use of a genotyping test for CYP2C19 metaboliser status is often advocated as a substitute for direct phenotyping with validated probe drugs such as OMP. However, genetic variability is not the only factor that can affect functional activity of drug-metabolising enzymes; gender, age and co-medications can all play a role in variable CYP expression. In particular, co-medications can mimic the genetic variability observed for CYP2C19 with the result that a patient can become a PM ‘phenocopy' due to inhibition (competition) of drug metabolism. However, the importance of chronic disease as a contributor to variable drug disposition is often overlooked. There is increasing evidence that the activity of CYP is decreased in cancer. In a small study of patients (n=16) with advanced cancer (Williams et al, 2000), all individuals had normal CYP2C19 genotype but 25% of these patients were CYP2C19 PM phenocopies. However, the mechanism behind this genotype–phenotype discordance was not investigated. Previous studies have demonstrated that the activity of a different enzyme, CYP3A4, is also decreased in advanced cancer patients and that the decreased activity correlates with inflammatory response (Rivory et al, 2002). An inverse relationship between plasma cytokine (TNF-α and IL-6) concentrations and CYP2C19 activity has been demonstrated in patients with congestive heart failure (Frye et al, 2002). Moreover, CYP2C19 mRNA expression is reported to be downregulated by cytokines in human hepatocyte in vitro cultures (Aitken and Morgan, 2007). Hence, limited evidence indicates that advanced cancer patients may have decreased capacity to metabolise certain chemotherapeutic agents due to decreased CYP activity. The aim of this study was to confirm whether or not CYP2C19 activity is decreased in patients with advanced cancer and to determine whether a relationship exists between CYP2C19 metaboliser status and inflammatory markers such as cytokines and acute phase response proteins.