CYP3A4 genetic polymorphism influences repaglinide's pharmacokinetics.
OBJECTIVE
To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide's pharmacokinetics in healthy Malaysian subjects.


METHODS
Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles.


RESULTS
The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide's blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide's pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide.


CONCLUSIONS
Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide's pharmacokinetics.
Department of Pharmacology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia. ruzila@kk.usm.my
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Ruzilawati
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SH
Gan
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000097:blood / Q000235:genetics*; D044466:Asian People; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011110:Polymorphism, Genetic; D055815:Young Adult
D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human