Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide.
OBJECTIVE
Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes.


METHODS
A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis.


RESULTS
St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype.


CONCLUSIONS
Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.
Xu
H
H
Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
Williams
K M
KM
Liauw
W S
WS
Murray
M
M
Day
R O
RO
McLachlan
A J
AJ
D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D005907:Gliclazide / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D041743:Herb-Drug Interactions; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010936:Plant Extracts; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D005907:Gliclazide