Effects of St John's wort andCYP2C9genotype on the pharmacokinetics and pharmacodynamics of gliclazide

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Abstract
Background and purpose: 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.Experimental approach: 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 (AUC0−∞), apparent clearance (CL/F) and elimination half‐life (t1/2) of gliclazide and incremental changes in glucose and insulin AUC0−4were compared.CYP2C9*2andCYP2C9*3alleles were identified using PCR followed by restriction enzyme digestion analysis.Key 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 AUC0−∞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 gliclazidet1/2, with mean ratio and 90% CI of 0.85 (0.74–0.93). There were no significant changes in glucose or insulin AUC0−4after St John's wort treatment and no significant differences according toCYP2C9genotype.Conclusions and implications: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent ofCYP2C9genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.British Journal of Pharmacology(2008)153, 1579–1586; doi:10.1038/sj.bjp.0707685; published online 21 January 2008

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