Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

Abstract

Accumulating evidence indicates that CYP2C9 ranks amongst the most important drug metabolizing enzymes in humans. Substrates for CYP2C9 include fluoxetine, losartan, phenytoin, tolbutamide, torsemide, S-warfarin, and numerous NSAIDs. CYP2C9 activity in vivo is inducible by rifampicin. Evidence suggests that CYP2C9 substrates may also be induced variably by carbamazepine, ethanol and phenobarbitone. Apart from the mutual competitive inhibition which may occur between alternate substrates, numerous other drugs have been shown to inhibit CYP2C9 activity in vivo and/or in vitro. Clinically significant inhibition may occur with coadministration of amiodarone, fluconazole, phenylbutazone, sulphinpyrazone, sulphaphenazole and certain other sulphonamides. Polymorphisms in the coding region of the CYP2C9 gene produce variants at amino acid residues 144 (Arg144Cys) and 359 (Ile359Leu) of the CYP2C9 protein. Individuals homozygous for Leu359 have markedly diminished metabolic capacities for most CYP2C9 substrates, although the frequency of this allele is relatively low. Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates. Individualisation of dose is essential for those CYP2C9 substrates with a narrow therapeutic index.

Lower frequency of CYP2C9*2 in Mexican-Americans compared to Spaniards

“…[3][4][5] The CYP2C9 isoenzyme is primarily responsible for the oxidative metabolism of several clinically important compounds, including the narrow therapeutic index drugs warfarin and phenytoin, and other routinely prescribed compounds such as losartan, tolbutamide and numerous nonsteroidal anti-inflammatory drugs such as ibuprofen, piroxicam, tenoxicam and diclofenac. 5 CYP2C9 exhibits marked interindividual variability in its expression and catalytic activity due to functionally significant genetic variations. This can result in either drug toxicity (eg, warfarin-induced bleeding complications) or therapeutic failure in some patients who take standard doses of CYP2C9 substrate drugs.…”

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

“…CYP2C9 is a genetically polymorphic cytochrome P450 enzyme that is responsible for the metabolism of many widely used drugs, such as warfarin, tolbutamide, phenytoin, losartan and many NSAIDs [6]. At present, six different allelic variants have been reported (http://www.imm.ki.se/CYPalleles).…”

“…At present, six different allelic variants have been reported (http://www.imm.ki.se/CYPalleles). In Caucasians, the frequency of the two most important allele variants, CYP2C9 * 2 and CYP2C9 * 3 , has ranges 8-12.5% and 3-8.5%, respectively, but lower frequencies have been reported for other ethnic groups [6,7]. The different alleles code for enzymes with different amino acid composition, and the functional significance of this polymorphism has been studied both in vitro and in vivo .…”

“…The different alleles code for enzymes with different amino acid composition, and the functional significance of this polymorphism has been studied both in vitro and in vivo . For several CYP2C9 substrates, metabolism by the CYP2C9.3 enzyme variant is markedly reduced compared to the enzyme encoded by CYP2C9 * 1 [6,8,9] . This has clinical implications for CYP2C9 drugs with narrow therapeutic windows, such as warfarin and phenytoin, where drug accumulation due to slow metabolism will increase the risk of severe adverse reactions [10][11][12].…”

Pungent ginger components modulates human cytochrome P450 enzymes in vitro

“…It also metabolizes endogenous substrates, such as arachidonic acid and linolenic acid. CYP2C9 inhibition is involved in increases in the plasma concentration and toxicity of concomitant substrate drugs of CYP2C9, especially those with a narrow therapeutic index (eg, warfarin and phenytoin) [31] . Therefore, these factors should be taken into consideration when ginger is consumed.…”