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. 2008 Jan 21;153(7):1579–1586. doi: 10.1038/sj.bjp.0707685

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide

H Xu 1, K M Williams 2, W S Liauw 2, M Murray 1, R O Day 2, A J McLachlan 1,3,*
PMCID: PMC2437900  PMID: 18204476

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 (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC0−4 were compared. CYP2C9*2 and CYP2C9*3 alleles 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 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 AUC0−4 after St John's wort treatment and no significant differences according to CYP2C9 genotype.

Conclusions and implications:

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.

Keywords: pharmacokinetics, pharmacodynamics, gliclazide, St John's wort, CYP2C9, genotype

Introduction

The incidence of type 2 diabetes is increasing in the community. Dietary modification and hypoglycaemic medicines such as gliclazide have important roles in the control of diabetes and the prevention of secondary complications of this disease. Recent survey data indicate that 52% of Australian consumers had used complementary and alternative medicines in 2004 (MacLennan et al., 2006). Approximately, half of these consumers also took prescription medicines at the same time (Kristoffersen et al., 1996; MacLennan et al., 2006). Furthermore, 31% of diabetic patients have been reported to take alternative medicines, most in conjunction with conventional medicines (Ryan et al., 2001). St John's wort (Hypericum perforatum) is one of the most widely used herbal medicines in Western countries, and it has been used for centuries for a variety of diseases, but most commonly for depression (Ryan et al., 2001). A systematic review of clinical trials concluded that St John's wort interacts with many medicines, including many clinically important drugs such as warfarin and cyclosporin, leading to reduced effectiveness (Mills et al., 2004).

Gliclazide (1-(3-azabicyclo[3.3.0]oct-3-yl)-3-para-tolylsulphonylurea) is a most widely used sulphonylurea drug for type 2 diabetes (Figure 1). The clinical use of gliclazide is initiated at 40 mg daily and may increase up to 320 mg daily in divided doses. It has high bioavailability (approximately 100%) from tablets and gliclazide's absorption is not affected by food (Shima et al., 1982; Hong et al., 1998). Compared to other sulphonylureas, gliclazide has an intermediate half-life of approximately 11 h (Campbell et al., 1991; Park et al., 2003). Gliclazide is extensively metabolized in the liver (Davis et al., 2000) to at least eight identified metabolites (Oida et al., 1985; Campbell et al., 1991; Taylor et al., 1996). Tolylmethyl hydroxylation (to form methyl-hydroxy-gliclazide) followed by oxidation to the corresponding carboxylic acid (to form carboxygliclazide) is the major metabolic pathway of gliclazide. These two metabolites account for 59% of the dose recovered in urine 96 h later (Oida et al., 1985). Hydroxylation of the azabicyclo-octyl moiety has the potential to form seven monohydroxylated metabolites. Four of these metabolites (6α, 6β, 7α and 7β positions) have been identified in urine, which represented 1, 20, 6 and 14% of urinary recovered dose 96 h after dose, respectively (Oida et al., 1985). Gliclazide metabolites have no hypoglycaemic activity and plasma concentrations are very low, representing only a small fraction of gliclazide concentrations in vivo (Campbell et al., 1980; Lupo and Bataille, 1987). There is no evidence that transporters are involved in gliclazide disposition. Elliot et al. (2007) recently identified the human cytochrome P450 catalysing the rate-limiting pathways of gliclazide metabolism and found that cytochrome P450 2C9 (CYP2C9) is the major contributor to gliclazide metabolic clearance, although CYP2C19 may also be involved in tolymethyl hydroxylation of gliclazide.

Figure 1.

Figure 1

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Chemical structure of gliclazide.

CYP2C9 is a polymorphic enzyme with 29 variant alleles described (www.cypalleles.ki.se/). The three most common alleles are CYP2C9*1 (wild-type), CYP2C9*2 and CYP2C9*3. CYP2C9*2 and CYP2C9*3 alleles are associated with lower enzyme activity both in vitro and in vivo (Lee et al., 2002; Soga et al., 2004; Topic et al., 2004). CYP2C9 polymorphism also plays an important role in individual differences in hypoglycaemic effects of sulphonylurea agents (Kirchheiner et al., 2005). The CYP2C9*2/*2 genotype carriers have a lower apparent clearance (CL/F) of glyburide compared to the individuals with CYP2C9*1/*1, but this contrast is not seen with the other sulphonylurea drugs. The carriers of one or two CYP2C9*3 alleles tend to have lower CL/F for most of the sulphonylurea drugs. However, there are only limited clinical data available on gliclazide pharmacokinetics and/or pharmacodynamics in relation to CYP2C9 genotype groups despite the suggestion that individual gene differences are potentially important factors that determine a patient's response to therapy.

The aims of this study were to investigate the effects of St John's wort on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects and to identify sources of individual variation by examining gliclazide pharmacokinetics and pharmacodynamics in relation to CYP2C9 polymorphisms.

Methods

Subjects

This study was approved by the St Vincent's Hospital and University of Sydney Human Research Ethics Committees (Sydney, Australia). A total of 21 healthy volunteers (15 male, 6 female; age range, 19–37 years; weight range, 53–91 kg) were recruited and screened for CYP2C9 genotype after giving written informed consent. Health status was assessed by medical history, physical examination and routine laboratory tests (including fasting blood glucose concentration).

Pharmacogenetic study (PCR-RFLP analysis)

Saliva (2 ml) or blood samples (4 ml) were obtained from each subject. DNA was extracted and used to detect the different alleles of CYP2C9. Genomic DNA was isolated from saliva using Oragene DNA Self-Collection Kit (DNA Genotek, Ottawa, ON, Canada) or blood using Qiagen blood kit (Qiagen, Doncaster, VIC, Australia). Detection of the CYP2C9*2 and CYP2C9*3 alleles were carried out using a polymerase chain reaction based restriction fragment length polymorphism (polymerase chain reaction-RFLP) analysis. The primers and restriction sites (AvaII restriction site for the CYP2C9*2 allele, NsiI and KpnI for the CYP2C9*3 allele) used in the present study were as described by Sullivan-Klose et al. (1996). Subjects in whom neither CYP2C9*2 nor CYP2C9*3 was detected were characterized as CYP2C9 wild type (*1/*1).

Briefly, PCR was performed in a final reaction volume of 50 μl, which included 20 μl 2.5 × HotMasterMix (Eppendorf, Westbury, NY, USA), approximately 250 ng of human genomic DNA and the primer pairs (0.25 μM). PCR amplification was performed with an initial melting step at 94 °C for 2 min, followed by 35 cycles of denaturation at 94 °C for 30 s, annealing at 55 °C for CYP2C9*2 (59 °C for CYP2C9*3) for 30 s and extension at 72 °C for 30 s. Upon completion of 35 cycles, the reaction was continued at 72 °C for 10 min for final extension. Aliquots of each PCR reaction (16 μl for AvaII and NsiI, 10 μl for KpnI) were subjected to restriction enzyme analysis with 20 U AvaII (CYP2C9*2) and NsiI (CYP2C9*3) or 10 U KpnI (CYP2C9*3). After overnight incubation at 37 °C, digested products were separated by electrophoresis using 2% agarose gels (Progen, Darra, QLD, Australia) run at 110 V for 60 min for CYP2C9*2 or 2.5% agarose gels run at 110 V for 50 min for CYP2C9*3; the gels were stained with ethidium bromide and the restriction fragments were visualized (Gel Doc, Bio-Rad, Segrate, Milan, Italy).

Clinical study

A sequential crossover two-treatment study was performed, with at least a 4-day washout period between the two treatments. After an overnight fast, a single dose of 80 mg gliclazide (Diamicron, Servier Laboratories, Hawthorn, VIC, Australia) was administered either alone or, on the last day (Day 15) treatment, with 300 mg St John's wort (Kira, LI 160 extract, Lichtwer Pharma, Berlin, Germany) given three times a day. An oral 75 g dose of glucose (Glucaid Clear, Fronine, Riverstone, NSW, Australia) was given 0.5 h after gliclazide intake. Food and drink (with the exception of water) were not allowed for the first 4 h after gliclazide intake. All participants were asked not to drink caffeine-containing beverages and to refrain from grapefruit from the day before until 2 days after taking gliclazide. Venous blood (EDTA tube) was taken for gliclazide and insulin quantification at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36 and 48 h after gliclazide administration. Plasma was obtained by centrifugation at 1500 g for 15 min and stored at −20 °C before the assay. Capillary blood samples were used to measure glucose levels at 0, 0.5, 1, 1.5, 2, 2.5, 3 and 4 h after gliclazide administration.

Analytical methods

Plasma gliclazide concentrations were measured by reversed-phase HPLC using a C18 column (150 × 4.6 mm) by the method of Park et al. (2004) with minor modifications. The separation was achieved using a mobile phase of 40 mM KH2PO4 (pH 4.6, 56%) and acetonitrile (44%) at a flow rate of 1.2 ml min−1 with UV detection at a wavelength of 227 nm. In brief, 0.5 ml of plasma, 20 μl of glibenclamide (internal standard, 50 μg ml−1) and 0.5 ml of acetonitrile was transferred to a 10 ml plastic tube. After vortexing for 10 s, chloroform (4 ml) was added followed by vigorous shaking (1 min) and then centrifugation at 1500 g for 15 min. The lower organic layer (3 ml) was transferred into a 5 ml glass tube and dried under a stream of nitrogen at 40 °C. The residue was reconstituted with mobile phase (150 μl), vortex mixed for 20 s, then transferred to a microcentrifuge tube and centrifuged at 1500 g for 2 min, and 50 μl of the upper layer was taken for HPLC analysis. The limit of detection for gliclazide was 50 ng ml−1. The intraday and interday coefficients of variation for gliclazide were all less than 11% at concentrations of 0.5, 3 and 8 μg ml−1 (n=5).

Plasma insulin concentration was determined using the Coat-A-Count 125I-labelled radioimmunoassay (Bio-Mediq DPC, Los Angeles, CA, USA). Capillary blood glucose concentration was measured immediately after each sample was taken using a commercial glucose meter (Roche ACCU-CHEK Go, Castle Hill, NSW, Australia).

Data analysis

The area under the plasma gliclazide concentration–time curve (AUC) up to the last concentration measured (AUC0–t) was determined using the linear trapezoidal rule. The AUC was extrapolated to infinity (AUCt–∞) using Ct/kel, where Ct is the last measured gliclazide concentration and kel is the elimination rate constant determined from the terminal slope of the log concentration–time plot. Elimination half-life (t1/2) was calculated as ln 2/kel. The maximum concentration (Cmax) and the time to Cmax (tmax) were obtained by the inspection of the concentration–time data. The CL/F was calculated as dose/AUC0–∞.

The glucose and insulin concentrations were measured to determine the pharmacodynamic effects. The incremental area under the blood glucose and insulin concentration–time curves (AUC0–4) were calculated to adjust for the individual variation of the baseline glucose concentrations using the approach described by Park et al. (2003). The maximum glucose and insulin concentration after glucose loading was determined by observation of the concentration–time data.

Statistical analysis

All data are presented as mean±s.d. and 95% confidence interval (CI) except tmax, which is presented as median and range. The pharmacokinetic parameters with and without St John's wort treatment were compared using the paired Student's t-test. The mean residual error was calculated using ANOVA (Stata 5.0, Stata Corp, College Station, TX, USA) of log-transformed parameters considering treatment and used to calculate the 90% CI of the ratio of log-transformed pharmacokinetic parameters comparing control (gliclazide alone) and treatment phase (gliclazide and St John's wort). A 90% CI that did not include 1.0 was considered significantly different.

Results

Effects of St John's wort on pharmacokinetics of gliclazide

St John's wort significantly reduced gliclazide AUC0–∞ and Cmax in 17 of 21 healthy subjects, and the results of all 21 subjects are presented here (Figures 2, 3). The mean ratio (n=21) and 90% CI of gliclazide AUC0–∞ and CL/F are shown in Table 1. After St John's wort treatment, gliclazide Cmax decreased by 22%, whereas the CL/F increased by nearly 50%. Furthermore, the mean t1/2 of gliclazide after St John's wort treatment decreased from 10.3 to 8.7 h.

Figure 2.

Figure 2

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Mean plasma gliclazide concentration–time profile in control and St John's wort treatment phases. Error bars represent s.d. (n=21).

Figure 3.

Figure 3

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Individual gliclazide (a) maximum plasma concentration (Cmax), (b) apparent clearance (CL/F) and (c) area under the plasma gliclazide concentration–time curve (AUC) in 21 healthy subjects after single oral dose of 80 mg gliclazide before and during co-administration with St John's wort (300 mg three times daily for 15 days).

Table 1.

Pharmacokinetic parameters of gliclazide in 21 healthy subjects after a single oral dose of 80 mg gliclazide or co-administered with St John's wort (300 mg three times daily)

Pharmacokinetic parameter Gliclazide alone Gliclazide and St John's wort Ratio (90% CI)
tmax (h) 5 (3–8) 4 (1.5–6) NA
Cmax (μg ml−1) 4.5 (3.9–5.0) 3.5 (3.0–4.0) 0.78 (0.72–0.85)
Half-life (h) 10.3 (9.1–11.4) 8.7 (7.8–9.6) 0.85 (0.74–0.93)
CL/F (l h−1) 1.5 (1.2–1.8) 2.2 (1.9–2.6) 1.50 (1.24–1.81)
AUC0–∞ (μg h ml−1) 67.2 (48.6–85.7) 43.6 (33.9–53.2) 0.67 (0.55–0.81)
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Abbreviations: AUC0–∞, area under the plasma gliclazide concentration–time curve extrapolated to infinity; CI, confidence interval; Cmax, maximum concentration; CL/F, apparent clearance; NA, not applicable; tmax, time to Cmax.

Ratio is presented as mean and 90% CI, and all others are presented as mean and 95% CI.

Effects of St John's wort on pharmacodynamics of gliclazide

Glucose concentration increased after the intake of 75 g glucose in each phase of this study. Gliclazide initially lowered glucose concentrations, which returned to baseline 2.5 h after glucose intake. The mean incremental glucose concentration showed a trend towards a decrease after St John's wort treatment, but this difference did not reach statistical significance (Table 2 and Figure 4a). Similarly, the mean insulin incremental concentration increased slightly in the St John's wort phase of the study compared to the control phase (Table 2 and Figure 4b). There was considerable interindividual variation observed for both glucose and insulin concentration–time profiles.

Table 2.

Pharmacodynamic effects of gliclazide in 21 healthy subjects after a single oral dose of 80 mg gliclazide or co-administered with St John's wort (300 mg three times daily)

Pharmacodynamic parameter Gliclazide alone Gliclazide and St John's wort
Blood glucose
 Glucose incremental AUC0–4 (mmol h l−1) 8.5±4.8 6.2±6.2
 Glucose AUC0–4 (mmol h l−1) 23±2.7 22.2±3.0
 Glucose Cmax (mmol l−1) 8.7±1.5 8.6±1.4
Glucose tmax (h) 1.2 (1–2.5) 1.1 (1–2)
     
Plasma insulin
 Insulin incremental AUC0–4 (mIU h l−1) 180.1±122.2 211.9±159.1
 Insulin AUC0–4 (mIU h l−1) 198.9±141.0 228.1±167.6
 Insulin Cmax (mIU l−1) 97.2±53.7 118.0±71.4
 Insulin tmax (h) 1.6 (1–2.5) 1.3 (1–2)
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Abbreviations: AUC0–4, incremental area under the blood glucose and insulin concentration–time curves; Cmax, maximum concentration; tmax, time to Cmax.

Data are presented as mean±s.d., except for tmax data, which are given as median and range.

Figure 4.

Figure 4

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Mean changes in (a) glucose concentrations and (b) insulin concentration in 21 healthy subjects after single oral dose of 80 mg gliclazide alone and during co-administration with St John's wort (300 mg three times daily for 15 days) (error bars represent s.d.).

Pharmacogenetic results

All subjects were genotyped for CYP2C9 genes (Table 3). The subjects were grouped into three categories *1/*1 (wild type), *1/*2 or *2/*2, and *1/*3 to compare the pharmacokinetic parameters. There was slightly lower CL/F of gliclazide in subjects carrying the CYP2C9*2 allele, but the difference did not reach statistical significance (Figure 5).

Table 3.

Genotype frequency and gliclazide CL/F in 21 subjects in gliclazide only phase

CYP2C9 genotype Samples (n) Frequency (%) Gliclazide CL/F (ml h−1 kg−1)
*1/*1 11 52.4 24.0 (19.0–28.9)
*1/*2 or 6 28.6 18.5 (15.2–21.7)
*2/*2 1 4.8  
*1/*3 3 14.3 25.4 (20.4–30.5)
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Abbreviation: CL/F, apparent clearance.

Data shown was not to represent population frequency; data are presented as median and range.

Figure 5.

Figure 5

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Gliclazide apparent clearance (CL/F) of three groups of CYP2C9 genotypes in gliclazide only phase. (‘—' indicates mean in each group, the solid circle represents a subject with CYP2C9*2/*2 genotype).

Discussion and conclusions

The mean CL/F of gliclazide in subjects possessing the CYP2C9*2 allele (homozygous and heterozygous combined) was approximately 25% lower than that observed in wild-type subjects. In similar studies, the CL/F ratios in subjects possessing at least one copy of the CYP2C9*2 allele (compared with wild-type subjects) were 0.88 for tolbutamide (Kirchheiner et al., 2002a) and 0.9 for glyburide (Kirchheiner et al., 2002b). Furthermore, the CL/F of gliclazide in subjects who were heterozygous for the CYP2C9*3 allele was not significantly different from wild-type subjects in the present study, which is consistent with the reported findings for glyburide (Kirchheiner et al., 2002b). By contrast, for carriers of the CYP2C9*3 allele, the CL/Fs of glipizide (Kidd et al., 1999) and tolbutamide (Kirchheiner et al., 2002a) were significantly different from wild-type subjects, with ratios of 0.18 and 0.58, respectively. Compared with wild-type individuals, the clearances of tolbutamide (Kirchheiner et al., 2002a) and glyburide (Kirchheiner et al., 2002b) were decreased by 50–84% in those carrying the CYP2C9*3/*3 genotype and by 41–54% in those of CYP2C9*2/*3 genotype.

In a study by Holstein et al. (2005), the clinical implications of CYP2C9 genotype in people receiving sulphonylurea agents were examined. It was found that the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes were associated with a higher risk of experiencing severe hypoglycaemia (Holstein et al., 2005). However, these genotypes were not found in the present study population, which is compatible with the reported frequencies in Caucasians of the CYP2C9*2 and CYP2C9*3 alleles of 0.014 and 0.04, respectively (Lee et al., 2002); thus, the impact of these genotypes on gliclazide pharmacokinetics could not be evaluated.

The apparent differences in the impact of the CYP2C9 genotype on the clearance of drug substrates may be attributable in part to contributions from other CYPs. Thus, evidence has been presented that CYP2C19 can also oxidize tolbutamide, at least in vitro, although the in vivo significance is uncertain (Lasker et al., 1998; Wester et al., 2000). CYP2C9 is believed to be the principal enzyme involved in gliclazide elimination by tolylmethyl hydroxylation, but CYP2C19 may also contribute (Elliot et al., 2007). Accordingly, the potential contributions of CYP2C19 allelic variants to the pharmacokinetics of oral hypoglycaemic agents such as tolbutamide and gliclazide cannot be excluded, and this might explain the lack of concordance between CYP2C9 genotype and gliclazide clearance. A recent study investigated the relative influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide in healthy Chinese subjects (Zhang et al., 2007). These researchers suggest a greater role for CYP2C19 polymorphisms than has been reported previously.

The major aim of the present study was to evaluate the impact of St John's wort treatment on gliclazide pharmacokinetics and pharmacodynamics. Co-administration of St John's wort over a 15-day period significantly decreased gliclazide AUC0–∞ and t1/2, which is consistent with increased CL/F. Park et al. (2003) reported a 70% reduction of gliclazide AUC and fourfold increase of CL/F of gliclazide after 6 days of rifampicin treatment. Induction of CYP2C9 is the most likely mechanism responsible for the effects of rifampicin and St John's wort. However, it is noteworthy that altered gliclazide pharmacokinetics in response to co-administered St John's wort was somewhat similar in subjects carrying CYP2C9 variant alleles.

Despite the observed pharmacokinetic changes for gliclazide, there was no apparent change in the incremental AUC0–4 for either glucose or insulin after St John's wort treatment. This finding is in contrast to the observations of Park et al. (2003) who investigated the interaction between rifampicin and gliclazide. The reason for the discrepancy is unclear, but may relate to differences in the magnitude of the induction between St John's wort and rifampicin. The extent of induction of gliclazide clearance and the decrease in AUC produced by St John's wort may have been insufficient to alter the pharmacodynamic response in individuals with normal insulin regulation. However, there may have been additional environmental factors, such as diet (Shaw, 2006), that could have contributed to the minimal impact on pharmacodynamics in the present study.

The extent to which gliclazide clearance was influenced by co-administered St John's wort varied considerably between subjects. Pronounced increases in CL/F were observed in a few subjects showing efficient induction of CYP2C9, but the majority of individuals exhibited relatively small changes, whereas in four subjects, gliclazide clearance decreased somewhat after treatment with St John's wort. The adherence to St John's wort treatment was established by regular telephone contact and confirmed by interview, which corroborated the compliance records submitted immediately after completion of the study. Therefore, we speculated that such variation in response might be related to differences in the inducibility of the CYP2C9 gene between individuals.

The mechanism underlying the St John's wort–gliclazide interaction has not been established unequivocally. However, St John's wort has been shown to induce the CYP3A4 gene and to increase the clearance of many CYP3A4 substrates, for example, indinavir (Piscitelli et al., 2000), simvastatin (Sugimoto et al., 2001), cyclosporin (Bauer et al., 2003) and midazolam (Dresser et al., 2003). Hyperforin, a major constituent of St John's wort, is a high-affinity ligand for the PXR (pregnane X-receptor), which is a nuclear receptor that regulates the induction of a battery of drug-metabolizing enzymes and transporters, including CYPs 2C9, 2C19, 2C8, 3A4 and MDR (multidrug resistance gene)1 (P-glycoprotein, P-gp) (Moore et al., 2000; Chen et al., 2004). Interestingly, the extent of the interaction between St John's wort and the CYP3A4 substrate cyclosporin has been shown to be related to hyperforin content (Mai et al., 2004). In the present study, a hyperforin-rich St John's wort extract LI 160 (Kira) was used (Wurglics et al., 2001), which is most likely to have mediated the induction of CYP2C9 and led to altered gliclazide pharmacokinetics observed in this study. Although CYP2C9 appears to be the major enzyme involved in gliclazide metabolism, the contributions of CYP2C19 and possibly CYP2C18 cannot be excluded (Elliot et al., 2007). Therefore, in addition to the CYP2C9 induction by St John's wort, the induction of CYP2C19 and possibly CYP2C18 may contribute to the observed decrease in gliclazide AUC.

The effect of St John's wort on CYP2C9 induction has been studied with several drugs. Our previous studies demonstrated that St John's wort constituents induced the metabolism of S-warfarin, another CYP2C9 substrate (Jiang et al., 2004). Wang et al. (2001) studied the prototypic sulphonylurea, tolbutamide, under conditions of short-term and long-term St John's wort co-administration but, somewhat surprisingly, neither of these treatments influenced the pharmacokinetic parameters of tolbutamide (Wang et al., 2001). However, the hyperforin content of the St John's wort preparation used by these researchers was not clearly defined, so that comparisons with the present study are not straightforward.

Despite the finding that allelic variants of CYP2C9 contribute to gliclazide pharmacokinetic differences, there are additional pharmacodynamic factors that could account for interindividual differences in glucose and insulin concentrations in response to gliclazide treatment. These factors include polymorphisms in genes encoding the pancreatic sulphonylurea receptor (SUR1 or ABCC8) and its endogenous ligand α-endosulphine (ENSA), potassium channels and other regulators of insulin secretion (Goksel et al., 1998; Elbein et al., 2001; Wang et al., 2004). Further study on variations of those genes involved in pharmacodynamic differences may help to better understand the findings of the present study.

St John's wort significantly decreased gliclazide AUC0–∞, which was probably due to induction of CYP2C9 and/or CYP2C19. Variant alleles of CYP2C9 did not appear to mediate differences in gliclazide clearance or glucose-lowering effects. Further investigations in people with diabetes will improve our understanding of the impact of pharmacogenetics on gliclazide pharmacokinetics and provide further insight into its optimal clinical usage and the effects of herbal remedies on the pharmacokinetics and pharmacodynamics of prescription medicines.

Acknowledgments

We are grateful to the medical and nursing staff at St Vincent's Clinical Trial Centre. We also thank Dr Gloria Quee for excellent technical advice on CYP genotyping. A part of this study was supported by a grant from the Australian National Health and Medical Research Council.

Abbreviations

AUC

area under the plasma gliclazide concentration–time curve

CI

confidence interval

CL/F

apparent clearance

Cmax

maximum concentration

CYP2C9

cytochrome P450 2C9

kel

elimination rate constant

tmax

time to Cmax

Conflict of interest

The authors state no conflict of interest.

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