The CYP2C9 polymorphism: from enzyme kinetics to clinical dose recommendations

Abstract

CYP2C9 is the major human enzyme of the cytochrome P450 2C subfamily and metabolizes approximately 10% of all therapeutically relevant drugs. Two inherited SNPs termed CYP2C9*2 (Arg144Cys) and *3 (Ile359Leu) are known to affect catalytic function. Numerous rare or functionally silent polymorphisms have been identified. About 35% of the Caucasian population carries at least one *2 or *3 allele. CYP2C9 metabolizes several oral hypoglycemics, oral anticoagulants, non-steroidal anti-inflammatory drugs and other drugs, including phenytoin, losartan, fluvastatin, and torsemide. In vitro studies with several drugs indicate that the Cys144 (.2) and Leu359 (.3) variants confer only about 70 and 10% of the intrinsic clearance of the wild-type protein (.1), respectively. The clinical pharmacokinetic implications of these polymorphisms vary depending on the enzymes contribution to total oral clearance. Several studies demonstrated that the CYP2C9 polymorphisms are medically important for non-steroidal anti-inflammatory drugs, for oral hypoglycemics, vitamin K antagonistic oral anticoagulants, and phenytoin. In particular, CYP2C9 polymorphisms should be routinely considered in therapy with oral anticoagulants where severe adverse events at initiation of therapy might be reduced by genotyping. CYP2C9 polymorphisms were also clinically associated with side effects of phenytoin, with gastric bleeding during therapy with non-steroidals and with hypoglycemia under oral hypoglycemic drugs. Data appear mature enough for the routine consideration of CYP2C9 genotypes in therapy with acenocoumarol, phenytoin, warfarin, and some other drugs. Nevertheless, it is advisable before the routine clinical use of these genotype data to rigorously test the benefits of genotype-based therapeutic recommendations by randomized controlled clinical trials.

Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes

“…Such genotype specific enzyme kinetic data appear to be substrate-dependent, i.e. the CLint ranging from 7% to 111% (the median CLint 60%, excluding the outlier values), Km from 17% to 157% (the median Km 94%) and Vmax from 8% to 100% (the median Vmax 53%) for CYP2C9.2 and the CLint from 2% to 57% (the median CLint 10%), Km from 18% to 825% (the median Km 325%) and Vmax from 4% to 130% (the median Vmax 30%) for CYP2C9.3 as compared with the respective data of CYP2C9.1 [39]. Contrary to the expectation from these in vitro enzyme kinetic data, however, the results of the current study indicate a significantly lower diclofenac 4′-hydroxylase activity in Chinese HLM than Caucasian HLM, which was mainly associated with a difference in Km.…”

Transcription Factor and Drug-Metabolizing Enzyme Gene Expression in Lymphocytes from Healthy Human Subjects

“…In addition, VDR probably regulates CYP3A4, CYP2C9, and CYP2B6 (Drocourt et al, 2002). Only limited information is available on the regulation of CYP3A5 expression, but it appears to be inducible via the GR, PXR, and CAR as for CYP3A4 (Daly, 2006) and CYP2C9 (Kirchheiner et al, 2004). CYP2C8 expression is regulated by CAR, PXR, GR, and hepatic nuclear factor 4␣ in the liver (Ferguson et al, 2005).…”

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

“…2,33 In vitro, torsemide's metabolism was not affected by the CYP2C9*2 polymorphism supposedly as torsemide induces an anodic shift of CYP2C9 in favour of catalytic activity. 2,19,34 Clinical effects of the CYP2C9*2 variant, however, may also be due to linkage with other polymorphism alike CYP2C8*3 35 (Figure 3) or differential contributions of other CYP2C enzymes. In our study, none of the haplotypes at the CYP2C locus including the CYP2C9*2 variant was associated with torsemide's metabolic phenotype ( Table 2).…”

“…2 Except for CYP2C8*2 and *3, CYP2C9*2 and *3 and CYP2C19*2 functional amino acid substitutions in CYP2C genes are rare in Caucasian populations (compare www.imm.ki.se/CYPalleles/). For CYP2C9 substrates, more than 80% of the interindividual variation in pharmacokinetics remain unexplained by the known polymorphisms.…”

“…Torsemide clearance was greatly reduced in carriers of the CYP2C9*3 variant but not in carriers of the CYP2C9*2 variant in accordance with in vitro findings. 2,19,21,22 Torsemide may therefore be a valuable CYP2C9 probe drug with specific properties compared to the other commonly used substrates tolbutamide, 23 warfarin [24][25][26] or losartan. 27 Phenotyping unselected samples has lead to the identification of functionally relevant genetic polymorphisms.…”