Effect of Genetic Polymorphisms in Cytochrome P450 (CYP) 2C9 and CYP2C8 on the Pharmacokinetics of Oral Antidiabetic Drugs

Abstract

Type 2 diabetes mellitus affects up to 8% of the adult population in Western countries. Treatment of this disease with oral antidiabetic drugs is characterised by considerable interindividual variability in pharmacokinetics, clinical efficacy and adverse effects. Genetic factors are known to contribute to individual differences in bioavailability, drug transport, metabolism and drug action. Only scarce data exist on the clinical implications of this genetic variability on adverse drug effects or clinical outcomes in patients taking oral antidiabetics. The polymorphic enzyme cytochrome P450 (CYP) 2C9 is the main enzyme catalysing the biotransformation of sulphonylureas. Total oral clearance of all studied sulphonylureas (tolbutamide, glibenclamide [glyburide], glimepiride, glipizide) was only about 20% in persons with the CYP2C9*3/*3 genotype compared with carriers of the wild-type genotype CYP2C9*1/*1, and clearance in the heterozygous carriers was between 50% and 80% of that of the wild-type genotypes. For reasons not completely known, the resulting differences in drug effects were much less pronounced. Nevertheless, CYP2C9 genotype-based dose adjustments may reduce the incidence of adverse effects. The magnitude of how doses might be adjusted can be derived from pharmacokinetic studies. The meglitinide-class drug nateglinide is metabolised by CYP2C9. According to the pharmacokinetic data, moderate dose adjustments based on CYP2C9 genotypes may help in reducing interindividual variability in the antihyperglycaemic effects of nateglinide. Repaglinide is metabolised by CYP2C8 and, according to clinical studies, CYP2C8*3 carriers had higher clearance than carriers of the wild-type genotypes; however, this was not consistent with in vitro data and therefore further studies are needed. CYP2C8*3 is closely linked with CYP2C9*2. CYP2C8 and CYP3A4 are the main enzymes catalysing biotransformation of the thiazolidinediones troglitazone and pioglitazone, whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. The biguanide metformin is not significantly metabolised but polymorphisms in the organic cation transporter (OCT) 1 and OCT2 may determine its pharmacokinetic variability. In conclusion, pharmacogenetic variability plays an important role in the pharmacokinetics of oral antidiabetic drugs; however, to date, the impact of this variability on clinical outcomes in patients is mostly unknown and prospective studies on the medical benefit of CYP genotyping are required.

Pharmacokinetics of Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Glimepiride Following Co-administration in Healthy Volunteers: A Randomised, Open-label, Crossover Study

“…As with other sulphonylureas, the use of glimepiride in patients with type 2 diabetes is associated with an increased risk of hypoglycaemia [13]. Glimepiride is extensively metabolised in the liver, mainly by CYP2C9 [14], and concomitant administration of agents that inhibit CYP2C9, such as gemfibrozil and fluconazole, has been shown to increase the risk of hypoglycaemia [15]. Empagliflozin does not inhibit CYP450 enzymes in vitro (unpublished data), so the potential for CYP-mediated drug interactions is unlikely, but cannot be ruled out.…”

The use of gliclazide in the mirror of the individualized sulfonylurea therapy

“…A farmakogenomika, génexpresszió-eltérések, genetikai polimorfi zmusok gyógyszer-metabolizmusra, illetve -hatásra gyakorolt szerepének vizsgálata klinikofarmakoló-giai elemzések mind hangsúlyosabb területe [5,36,37,38]. Egyre nő a SU-kal kapcsolatos közlések száma is.…”

“…Az enzim génjének CYP2C9*3/*3 variánsa régóta ismert, a homozigóta formával rendelkezők esetében a tolbutamid, glibenclamid, glimepirid és glipizid clearence-e átlagosan csak 20%-a a természetes (elsőd-leges, "vad") variánssal (CYP2C9*1/*1) rendelkezőké-nek (azaz esetükben elhúzódóbb gyógyszerhatással kell számolni) [36,37]. Egy vizsgálatban a tolbutamid eseté-ben a homozigóta *3/*3 allélt hordozók clearence-ét 6,5-szer, a glimepiridét 0,5-szer kisebbnek találták a "vad" (*1/*1) allélt hordozókénál [5].…”

“…A CYP2C9*3/ *3 heterozigóták esetében a clearence az elsődleges változa túak 50-80%-a. A glibenclamid és a glimepirid lebom lásakor aktív metabolitok is képződnek, az elimináció elhúzódása a metabolitok vércukorcsökkentő hatá-sát is megnyújtja [36].…”

“…Felmérések szerint a kaukázusi rasszhoz tartozók 82%-ában a "vad", *1/*1 változat, 11%-ában a *2/*2 variáns, 7%-ában a *3/*3 forma található [36]. Megfigyelték, hogy az eddig kevéssé tanulmányozott *2/*2 variánssal, illetve a homozigóta *3/*3 alléllel rendelkezők körében jóval magasabb a célértékre kezeltek (HbA 1c <7,0%) aránya a "vad" típussal rendelkezőkéhez képest [5].…”