The discovery of six distinct polymorphisms in the genetic sequence encoding for the cytochrome P450 2C9 (CYP2C9) protein has stimulated numerous investigations in an attempt to characterize their population distribution and metabolic activity. Since the CYP2C9*1, *2 and *3 alleles were discovered first, they have undergone more thorough investigation than the recently identified *4, *5 and *6 alleles. Population distribution data suggest that the variant *2 and *3 alleles are present in approximately 35% of Caucasian individuals; however, these alleles are significantly less prevalent in African-American and Asian populations. In-vitro data have consistently demonstrated that the CYP2C9*2 and *3 alleles are associated with significant reductions in intrinsic clearance of a variety of 2C9 substrates compared with CYP2C9*1; however, the degree of these reductions appear to be highly substrate-dependent. In addition, multiple in-vivo investigations and clinical case reports have associated genotypes expressing the CYP2C9*2 and *3 alleles with significant reductions in both the metabolism and daily dose requirements of selected CYP2C9 substrates. Individuals expressing these variant genotypes also appear to be significantly more susceptible to adverse events with the narrow therapeutic index agents warfarin and phenytoin, particularly during the initiation of therapy. These findings have subsequently raised numerous questions regarding the potential clinical utility of genotyping for CYP2C9 prior to initiation of therapy with these agents. However, further clinical investigations evaluating the metabolic consequences in individuals expressing the CYP2C9*2, *3, *4, *5, or *6 alleles are required before large-scale clinical genotyping can be recommended.

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.

The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.

Rifampin is a potent inducer of losartan and E3174 elimination. Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.

CYP2C9 genotype is a significant predictor of flurbiprofen disposition in humans by altering CYP2C9-mediated metabolism and reducing systemic clearance. The effects are most pronounced in individuals carrying the *3 allele.