Gan Siew, Hua
(2008)
Genetic polymorphisms of cyp3a4 and cyp2c8 in heal thy volunteers administered with
repaglinide.
Universiti Sains Malaysia.
(Submitted)
Abstract
Repaglinide is a novel prandial glucose regulator (PGR) for the treatment of
type 2 diabetes mellitus. Repaglinide is mainly metabolised in the liver by CYP3A4
and CYP2C8 enzymes. The objective of the present study is to investigate the
effects of the CYP3A4 and CYP2CB genotypes on the pharmacokinetics of
repaglinide in 121 healthy Malaysian subjects.
The study protocol was approved by our local Research and Ethics
Committee, School of Medical Sciences, Universiti Sains Malaysia. Initially, a new
HPLC method using a simple liquid-liquid extraction for the determination of
repaglinide in human serum was developed and later validated. Then, PCR methods
were optimized to detect CYP3A4 and CYP2CB genetic polymorphisms among
healthy Malaysian subjects.
Each subject received 4 mg of oral repaglinide. Six blood samples per
individual were taken (0 min, 30 min, 60 min, 120 min, 180 min and 240 min) for
repaglinide's serum concentration determination by using HPLC. NPAG was then
used to determine population pharmacokinetic parameter values of repaglinide.
The developed HPLC method was selective and calibration curves of
repaglinide were found to be linear in the concentration range of 20-200 ng/ml. The
limits of detection (LOD) and quantification (LOQ) were 10 ng/ml and 20 ng/ml,
respectively. The inter-day precision was from 5.21% to 11.84o/o while the intra-day
precision ranged from 3.90°/o to 6.67%. The inter-day accuracy ranged between
89. 95°/o and 105. 75o/o with the intra-day accuracy ranging from 92.37% to 1 04.66°/o.
No mutations were detected for the CYP3A4*4 and CYP3A4*5 alleles. The
frequency of the CYP3A4*18 allele was 2.07o/o. All five subjects with CYP3A4*18
mutations were found to be heterozygous. For CYP2C8, the allele frequency for both
CYP2C8*2 and *3 was 0.4°/o while the allele frequency for CYP2C8*5 was 4.13°/o. All
subjects with mutations were found to be heterozygous.
No mutation was detected for the CYP2C8*4 allele. CYP2CB and CYP3A4
genotypes were not significantly associated with changes in the blood glucose
lowering effect of repaglinide. On the other hand, the CYP3A4 genotype significantly
influenced repaglinide's pharmacokinetics where the mean elimination rate constant
(kel) was 34°/o lower (p = 0.04) and the mean half-life (t112) was 133% longer (p =
0.04) i.n .. subjects having the CYP3A4*1/*18 genotype compared to those having the
CYP3A4*11*1 genotype.
In conclusion, CYP3A4 activity plays an important role in influencing
repaglinide's pharmacokinetics. Therefore, subjects having CYP3A4*11*18 may need
to receive lower doses of repaglinide.
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