Abstract
Aims: Sulfonylureas are mainly metabolized by the enzyme CYP2C9. Two allelic variants, CYP2C9*2 and CYP2C9*3, result in decreased metabolic capacity and have been associated with elevated sulfonylurea serum levels. However, most of the available data originates from pharmacokinetic analyses performed in healthy individuals. In this study, the effect of CYP2C9*2 and CYP2C9*3 alleles on prescribed dose and time-to-stable dose of sulfonylureas was investigated. Materials & methods: A group of 207 incident sulfonylurea users treated in four university affiliated primary care centers were identified. The effect of the CYP2C9*2 and CYP2C9*3 alleles on prescribed dose and time-to-stable dose was then assessed. Results: No significant effects of the CYP2C9*2 and CYP2C9*3 alleles were found. However, a trend towards a lower stable glimepiride dose for carriers of the CYP2C9*3 allele was observed. Conclusion: Genotyping for the CYP2C9*2 and CYP2C9*3 alleles currently appears to have no clinical implications for dosing of sulfonylureas in primary care patients with Type 2 diabetes mellitus.
Papers of special note have been highlighted as: ▪ of interest
Bibliography
- 1 Krentz AJ, Bailey CJ: Oral antidiabetic agents: current role in Type 2 diabetes mellitus. Drugs65(3),385–411 (2005).
- 2 Jennings AM, Wilson RM, Ward JD: Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care12(3),203–208 (1989).
- 3 Kirchheiner J, Brockmoller J, Meineke I et al.: Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin. Pharmacol. Ther.71(4),286–296 (2002).
- 4 Yin OQ, Tomlinson B, Chow MS: CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects. Clin. Pharmacol. Ther.78(4),370–377 (2005).
- 5 Shon JH, Yoon YR, Kim KA et al.: Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans. Pharmacogenetics12(2),111–119 (2002).
- 6 Kirchheiner J, Bauer S, Meineke I et al.: Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers. Pharmacogenetics12(2),101–109 (2002).
- 7 Wang R, Chen K, Wen SY, Li J, Wang SQ: Pharmacokinetics of glimepiride and cytochrome P450 2C9 genetic polymorphisms. Clin. Pharmacol. Ther.78(1),90–92 (2005).
- 8 Suzuki K, Yanagawa T, Shibasaki T, Kaniwa N, Hasegawa R, Tohkin M: Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with Type 2 diabetes. Diabetes Res. Clin. Pract.72(2),148–154 (2006).
- 9 Zhang Y, Si D, Chen X et al.: Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. Br. J. Clin. Pharmacol.64(1),67–74 (2007).
- 10 Ragia G, Petridis I, Tavridou A, Christakidis D, Manolopoulos VG: Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas. Pharmacogenomics10(11),1781–1787 (2009).
- 11 Holstein A, Plaschke A, Ptak M et al.: Association between CYP2C9 slow metabolizer genotypes and severe hypoglycaemia on medication with sulphonylurea hypoglycaemic agents. Br. J. Clin. Pharmacol.60(1),103–106 (2005).▪ First to report an association between the CYP2C9*3/*3 and *2/*3 genotypes and severe hypoglycemia.
- 12 Becker ML, Visser LE, Trienekens PH, Hofman A, van Schaik RH, Stricker BH: Cytochrome P450 2C9 *2 and *3 polymorphisms and the dose and effect of sulfonylurea in Type 2 diabetes mellitus. Clin. Pharmacol. Ther.83(2),288–292 (2008).▪ First population-based study assessing the clinical relevance of CYP2C9 polymorphisms in diabetes mellitus patients.
- 13 Zhou K, Donnelly L, Burch L et al.: Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in Type 2 diabetes: a go-DARTS study. Clin. Pharmacol. Ther.87(1),52–56 (2009).▪ Large study assessing the effect of CYP2C9 polymorphisms on a cohort of Type 2 diabetes patients treated mainly with gliclazide monotherapy.
- 14 Rutten GEHM, De Grauw WJC, Nijpels G et al.: NHG-Standard diabetes mellitus Type 2. Huisarts Wet.49(3),137–152 (2006).
- 15 van LoenenAC: Farmacotherapeutisch Kompas 2010. van Loenen AC, Sitsen JMA (Eds). College voor zorgverzekeringen, Diemen, The Netherlands (2010).
- 16 van den Berg MJ, de Bakker DH, Spreeuwenberg P et al.: Labour intensity of guidelines may have a greater effect on adherence than GPs’ workload. BMC Fam. Pract.10,74 (2009).
- 17 Lin Y, Sun Z: Current views on Type 2 diabetes. J. Endocrinol.204(1),1–11 (2009).
- 18 Ridderstrale M, Groop L: Genetic dissection of Type 2 diabetes. Mol. Cell Endocrinol.297(1–2),10–17 (2009).
- 101 Human cytochrome P450 (CYP) allele nomenclature committee www.cypalleles.ki.se/cyp2c9.htm (Accessed 1 November 2010)