Introduction cytochrome P450 2C9 (CYP2C9), have also been

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Introduction cytochrome P450 2C9 (CYP2C9), have also been

Introduction

 

Approximately 8.5 million sulphonylurea
prescriptions are filled annually in England for the management of type 2
diabetes (T2D)(1). Sulphonylureas are widely used anti-hyperglycaemic drugs which
stimulate insulin release from pancreatic ? cells in a
glucose-independent manner(2, 3). However, they have shown to demonstrate significant interpatient
variability in dose requirements, and have a narrow therapeutic index(3). Sulphonylureas can cause drug-associated hypoglycaemia, resulting
from duration of sulphonylurea action, excessive alcohol intake, irregular
eating patterns, age, mild baseline hyperglycaemia, and/or other mechanisms
beyond these clinical variables(3).

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Genetic variants that influence the activity
of the enzyme involved in sulphonylureas’ primary metabolism pathway,
cytochrome P450 2C9 (CYP2C9), have also been suggested among the predictors of sulphonylurea
efficacy and adverse events(3). Sulphonylureas are metabolised in the liver, principally by CYP2C9,
to less active metabolites which are subsequently excreted by the kidneys(3). In terms of drug-metabolising enzyme polymorphisms, CYP2C9*3 (Ile359Leu) and to a lesser
extent CYP2C9*2 (Arg144Cys),
influence the pharmacokinetics of many sulfonylureas(3). These CYP2C9
polymorphisms are loss-of-function variants which result in reduced enzyme
activity and impaired substrate metabolism, corresponding to increased blood
sulphonylureas levels(4).

 

Zhou et
al. conducted a large genotype-guided trial to examine the impact of
loss-of-function CYP2C9 variants on glycaemic
response to sulfonylureas(5). They found that patients with two copies of a loss-of-function
allele were more likely to achieve a treatment haemoglobin A1c (HbA1c)
level

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