A mutation in CYP2C9 is responsible for decreased metabolism of losartan.

Abstract

Clinical Pharmacology & Therapeutics (1996) 59, 215–215; doi:

Polymorphic Variants (CYP2C9*3 and CYP2C9*5) and the F114L Active Site Mutation of CYP2C9: Effect on Atypical Kinetic Metabolism Profiles

“…Similar reductions in metabolizing capacity were observed in patients heterozygous for the Leu359 allele and receiving phenytoin (Hashimoto et al, 1996). The homozygous Leu359 allele has been associated with the poor metabolizer phenotype for tolbutamide (Sullivan-Klose et al, 1996;Bhasker et al, 1997), warfarin (Steward et al, 1997), phenytoin and glipizide (Kidd et al, 1999), and losartan (Spielberg et al, 1996). With respect to the Glu360 variant (CYP2C9*5), Dickmann et al (2001) reported that this amino acid substitution increases the K m for the in vitro metabolism of S-warfarin, diclofenac, and lauric acid, with more modest effects on V max .…”

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

“…No other mutations were found in the coding region, intron‐exon junctions or upstream region of the CYP2C9 gene of this subject. Sequencing of the coding region of the CYP2C9 gene of two subjects identified as poor metabolisers of losartan similarly confirmed that both were homozygous for the mutation causing the Ile to Leu substitution at residue 359 [127]. Somewhat surprisingly, it therefore appears that the conserved Ile to Leu (both being structurally similar hydrophobic amino acids) substitution gives rise to the poor metaboliser CYP2C9 activity phenotypes.…”

“…Consistent with the tolbutamide population data, the frequency of the poor phenytoin hydroxylation phenotype has been estimated to be 1 in 500 based on the results of a pedigree analysis study [125, 126]. Furthermore, in clinical trials conducted in recent years with losartan, less than 1% of the subjects studied showed markedly diminished conversion of losartan to its active metabolite (a known CYP2C9 catalysed reaction) [127].…”

Genetic polymorphisms and functional characterization of the 5′-flanking region of the human CYP2C9 gene: In vitro and in vivo studies

“…Allele‐specific sequence analysis of the CYP2C9*3 allele in all 183 individuals indicated a strong association of the *3 allele with the pattern 2 promoter variant. With regard to the CYP2C9*3 allele, various in vivo studies revealed that patients or healthy individuals who were genotyped as homozygotes or heterozygotes of CYP2C9*3 exhibited significantly reduced metabolic activity for S ‐warfarin, 1 phenytoin, 2 tolbutamide, 3 and losartan 23 compared with those genotyped as homozygotes of CYP2C9*1 . Recently, Raimundo et al 24 reported an association between a mutation in the promoter region (–1496C to G) and the functional *2 allele in the CYP2D6 gene.…”