Influence Of Acetylator Phenotypes On Pharmacokinetics Of Gliclazide In Type 2 Diabetes Mellitus Patients

H Htet1, NHH Win2. 1SEGi University, Kuala Lumpur, Malaysia, 2University of Medicine (1) Yangon, Yangon, Myanmar

Type 2 diabetes mellitus is one of the most important non-communicable diseases which have become a big economical and social burden in the modern world. Gliclazide is one of the most popular sulphonylurea drugs in the management of type 2 diabetes mellitus. Many studies showed that acetylator phenotypes have influence on pharmacokinetics of many drugs. One study showed that gliclazide is metabolized into p-toluene sulphonamide (1). The chemical structure of p-toluene sulphonamide has amide group (-NH2) which is susceptible to metabolised by acetylation. Nitrazepam is a drug which does not possess amide group at first and only possesses after metabolism and this metabolites is proved to be metabolised by acetylation (2, 3). One study also stated that acetylation is one of the pathways of sulphonylurea metabolism (4).

The study was done on 15 volunteers of each rapid and slow acetylator type 2 diabetes mellitus patients by administering single oral dose of 80 mg immediate gliclazide. Plasma samples were taken at specific times of 0,1.5, 3,5,7 and 10 hours. The analysis of plasma concentration of gliclazide was carried out by HPLC with UV Vis detector method (5).

This study found that there were significant differences in absorption rate constant (Kab) (0.58 ± 0.32 and 1.05 ± 0.51 hr-1), absorption half life (T½ ab) (1.46 ± 0.57 and 0.85 ± 0.50 hr), time to reach maximum plasma concentration (Tmax) (4.6 ± 0.83 and 3.53 ± 0.92 hr), elimination rate constant (Kel) (0.073 ± 0.0073 and 0.063 ± 0.006 hr-1) and elimination half life (T½ el) (9.5 ± 0.37 and 11.11 ± 1.17 hr) between rapid and slow acetylators. Clearance is also more rapid in rapid acetylators (17.07 ± 4.77 mL.hr-1.kg-1). Area under concentration (AUC0- α) was smaller in rapid acetylators (84.15 ± 18.09 and 98.25 ± 0.34 μg.mL-1.hr-1). But no significant differences were found between maximum plasma concentration (Cmax), volume of distribution (Vd) and area under concentration curve (AUC0-10) between rapid and slow acetylators.

All in all, faster elimination and slower absorption was found in rapid acetylators and slower elimination and quicker absorption was found in slow acetylators. Although time to reach maximum plasma concentration were different in two acetylator phenotypes, maximum plasma concentration achieved was found to be the same. Therefore, it can be concluded as care should be taken in type 2 diabetes mellitus patients who are taking gliclazide as there can be alterations of plasma concentrations of gliclazide according to the individual’s acetylator phenotype.

References

1. Kobayashi et al. (1984) Journal of Pharmaceutical Science 73(12): 1684-7.

2. Karim et al. (1976) Journal of Medical Genetics 13: 17-19.

3. Miller et al. (1981) Clin Pharmacol Ther 30(3): 343-347.

4. Banjoko and Akinlade (2010) Ind J Clin Biochem 25(3): 289-294.