影响华法林抗凝血作用的有关因素

华法林为口服抗凝血药,用于治疗和预防血栓栓塞性疾病。华法林抗凝血作用(增强或减弱)受多种因素影响。这些因素包括遗传、疾病、药物、草药以及食物等。CYP2C9多态性(主要为CYP2C9*2、CYP2C9*3)、肝功能低下、甲状腺功能亢进、心力衰竭以及阿司匹林、氯吡格雷、咪康唑、当归、茴香、芹菜、菠萝、洋葱、大蒜等和华法林的相互作用均能致华法林抗凝血作用增强。而VKORC1的基因突变以及利福平、卡马西平、人参、绿茶,富含维生素K的制剂或饮食等和华法林相互作用均能使华法林抗凝血作用减弱。另外,有些药物如:苯妥英钠,既能增强又能减弱华法林的抗凝血作用。了解这些因素对华法林抗凝血作用的影响,定期监测INR值,进行个体化给药,有利于华法林安全有效应用。     

Interaction potential between cranberry juice and warfarin.

PURPOSE: The interaction potential between warfarin and cranberry juice is discussed. SUMMARY: Reports from the United Kingdom have raised concern over the interaction potential between cranberry juice and warfarin. Warfarin is the most commonly prescribed oral medication for anticoagulation therapy. Cranberry juice is a flavonoid, which has been shown to induce, inhibit, or act as a substrate for the biosynthesis of several cytochrome P-450 (CYP) isoenzymes. Specifically, cranberry juice may inhibit the activity of CYP2C9, the primary isoenzyme involved in the metabolism of S-warfarin. A search of the medical literature identified three peer-reviewed case reports and two peer-reviewed, prospective, randomized, placebo-controlled clinical trials using metabolic surrogates of warfarin (flurbiprofen and cyclosporine) that described possible interactions between cranberry juice and warfarin. Two case reports suggested that cranberry juice increased the International Normalized Ratio (INR) of patients taking warfarin, but neither clearly identified cranberry juice as the sole cause of INR elevation. One case report appeared to show a correlation between the effects of cranberry juice and warfarin metabolism. Both clinical trials indicated the lack of an interaction between cranberry juice and CYP isoenzymes 2C9 and 3A, both of which are necessary in warfarin metabolism. More studies are required to determine the potential interaction between cranberry juice and warfarin. CONCLUSION: The available data do not seem to show a clinically relevant interaction between cranberry juice and warfarin; however, patients taking warfarin with cranberry juice should be cautioned about the potential interaction and monitored closely for INR changes and signs and symptoms of bleeding.     

Pharmacokinetic and pharmacodynamic variation associated with VKORC1 and CYP2C9 polymorphisms in Thai patients taking warfarin

We investigated the influence of genetic polymorphisms of CYP2C9 and VKORC1 genotypes on the pharmacokinetics and pharmacodynamics of warfarin and established an equation for predicting the maintenance dose of warfarin in the Thai population using genetic and non-genetic factors. The CYP2C9*2, CYP2C9*3, VKORC1 C1173T and VKORC1 G-1639A genotypes were detected by realtime PCR using fluorogenic hybridization probes. The associations between genetic and demographic factors with respect to warfarin dosage were analyzed. CYP2C9 polymorphisms affect warfarin metabolism as shown by a significant difference in warfarin clearance, whereas VKORC1 genotypes cause a significant difference in warfarin sensitivity index (INR:Cp). The mean weekly warfarin dose was significantly different among different VKORC1 and CYP2C9 genotypes. Patients with the VKORC1 BB haplotype and CYP2C9*1/*1 required about twice the warfarin dose compared to those with the VKORC1 AA haplotype and CYP2C9*1/*1. Using stepwise multiple linear regression, clinical factors (age and weight) and genetic factors (CYP2C9 and VKORC1) could explain about 53.8% of the variance of the warfarin maintenance dose. CYP2C9 and VKORC1 genotypes played an important role in the inter-individual variation in warfarin maintenance dose in a Thai population.     

Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Cranberry juice has a significant inhibitory effect on CYP2C9 activity in vitro , whereas it shows a minimal effect on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate in vivo .
• Information regarding the interaction between cranberry juice and other medications metabolized by CYP2C9 is limited.
WHAT THIS STUDY ADDS
• Cranberry juice suppressed the metabolism of diclofenac, another CYP2C9 substrate, by human liver microsomes.
• Pharmacokinetic parameters of diclofenac were not altered by cranberry juice consumption in human subjects.  

AIM

To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9.  

METHODS

The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics.  

RESULTS

Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects.  

CONCLUSIONS

Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro , it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.     

Pharmacokinetics of Cinacalcet Hydrochloride When Administered with Ketoconazole

BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole. SUBJECTS AND METHODS: Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms. RESULTS: Twenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments. CONCLUSIONS: Co-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.     

Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations

OBJECTIVES: Polymorphism in the genes for cytochrome (CYP)2C9 and the vitamin K epoxide reductase complex subunit 1 (VKORC1) affect the pharmacokinetics and pharmacodynamics of warfarin. We developed and validated a warfarin-dosing algorithm for a multi-ethnic population that predicts the best dose for stable anticoagulation, and compared its performance against other regression equations. METHODS: We determined the allele and haplotype frequencies of genes for CYP2C9 and VKORC1 on 167 Caucasian, African-American, Asian and Hispanic patients on warfarin. On a subset where complete data were available (n=92), we developed a dosing equation that predicts the actual dose needed to maintain target anticoagulation using demographic variables and genotypes. This regression was validated against an independent group of subjects. We also applied our data to five other published warfarin-dosing equations. RESULTS: The allele frequency for CYP2C9*2 and *3 and the A allele for VKORC1 3673 was similar to previously published reports. For Caucasians and Asians, VKORC1 SNPs were in Hardy-Weinberg linkage equilibrium. Some VKORC1 SNPs among the African-American population and one SNP among Hispanics were not in equilibrium. The linear regression of predicted versus actual warfarin dose produced r-values of 0.71 for the training set and 0.67 for the validation set. The regression coefficient improved (to r=0.78 and 0.75, respectively) when rare genotypes were eliminated or when the 7566 VKORC1 genotype was added to the model. All of the regression models tested produced a similar degree of correlation. The exclusion of rare genotypes that are more associated with certain ethnicities improved the model. CONCLUSION: Minor improvements in algorithms can be observed with the inclusion of ethnicity and more CYP2C9 and VKORC1 SNPs as variables. Major improvements will likely require the identification of new gene associations with warfarin dosing.     

Drug interactions with herbal medicines

In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes and/or drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic and/or pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St John's wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms.     

Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population

Purpose

The aim of this study was to assess the pharmacokinetics and pharmacodynamics of warfarin associated with genetic polymorphisms in VKORC1, CYP2C9, CYP2C19, and CYP4F2 in Indonesian patients treated with low-dose warfarin.

Methods

Genotyping of VKORC1, CYP2C9, CYP2C19, and CYP4F2 was carried out in 103 patients treated with a daily dose of 1–2 mg warfarin, 89 of whom were treated with a fixed daily dose of warfarin (1 mg). The plasma concentrations of S- and R-warfarin and S- and R-7-hydroxywarfarin were used as pharmacokinetic indices, while prothrombin time expressed as the international normalized ratio (PT-INR) was used as a pharmacodynamic index.

Results

In patients treated with a fixed daily dose of warfarin (1 mg), a higher PT-INR was associated with VKORC1-1639 AA [median 1.35; interquartile range (IQR)?1.21–1.50] than with the GA (1.18; IQR?1.12–1.32; p?<?0.01) and GG (1.02; IQR?=?1.02–1.06; p?<?0.01) polymorphisms, and with CYP2C9*1/*3 (1.63; IQR?1.45–1.85) compared to *1/*1 (1.23; IQR??1.13–1.43; p?<?0.05). The S-warfarin concentration was significantly higher in patients with CYP2C9*1/*3 than in those with *1/*1 (p?<?0.05). With low-dose warfarin administration, there was no significant difference in the concentrations of warfarin metabolites among any of the genotype variants. The genotype variations of CYP2C19 and CYP4F2 were not significantly associated with the PT-INR.

Conclusion

For low-dose warfarin treatment, the VKORC1-1639 G?>?A and CYP2C9 genotype variations affected the pharmacokinetics and pharmacodynamics of warfarin, while we could not find significant effects of CYP4F2 or CYP2C19 genotype variations on warfarin (metabolite) concentrations or PT-INR.     

Warfarin and vitamin K intake in the era of pharmacogenetics

The considerable variability in the warfarin dose–response relationship between individuals, is explained mainly by genetic variation in its major metabolic (CYP2C9) and target (VKORC1) enzymes. Despite the predominance of pharmacogenetics, environmental factors also affect the pharmacokinetics and pharmacodynamics of warfarin, and are often overlooked. Among these factors, dietary and supplemental vitamin K consumption is a controllable contributor to within-, and between-patient variability of warfarin sensitivity. In this commentary we review the current role of vitamin K in warfarin anticoagulation therapy, with emphasis on the following:

1. The effect of dietary and supplemental vitamin K on warfarin anticoagulation, beyond the impact of genetic variability in CYP2C9 and VKORC1. We deal separately with the effects of vitamin K on warfarin dose requirements during the induction of therapy, as opposed to its effect on stability of anticoagulation control during maintenance therapy.
2. The role of vitamin K supplementation in warfarin treated patients with vitamin K deficiency as well as in patients with unstable warfarin anticoagulation, and
3. The role of therapeutic vitamin K in cases of warfarin over-anticoagulation.

     

Inhibitory effect of six herbal extracts on CYP2C8 enzyme activity in human liver microsomes

Abstract

1.?Herbal supplements widely used in the US were screened for the potential to inhibit CYP2C8 activity in human liver microsomes. The herbal extracts screened were garlic, echinacea, saw palmetto, valerian, black cohosh and cranberry. N-desethylamodiaquine (DEAQ) and hydroxypioglitazone metabolite formation were used as indices of CYP2C8 activity.

2.?All herbal extracts showed inhibition of CYP2C8 activity for at least one of three concentrations tested. A volume per dose index (VDI) was calculated to determine the volume in which a dose should be diluted to obtain IC₅₀ equivalent concentration. Cranberry and saw palmetto had a VDI value >5.0?l per dose unit, suggesting a potential for interaction.

3.?Inhibition curves were constructed and the IC₅₀ (mean?±?SE) values were 24.7?±?2.7?μg/ml for cranberry and 15.4?±?1.7?μg/ml for saw palmetto.

4.?The results suggest a potential for cranberry or saw palmetto extracts to inhibit CYP2C8 activity. Clinical studies are needed to evaluate the significance of this interaction.     

The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype

AIMS

1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype.

METHODS

A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h.

RESULTS

Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUC_PT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUC_PT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUC_{PT((R)-warfarin)} : AUC_{PT((S)-warfarin)}) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype.

CONCLUSIONS

(R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.     

Warfarin dosing and the promise of pharmacogenomics

Due to its narrow therapeutic index and substantial inter-patient variability in clinical response, warfarin represents an ideal drug candidate to benefit from the promise of pharmacogenomic-guided dosing strategies. Consistent with in vitro data, clinical studies have demonstrated that CYP2C9 polymorphisms significantly influence warfarin pharmacokinetics by reducing (S)-warfarin metabolic clearance, consequently lowering maintenance dose requirements and increasing the risk over-anticoagulation during the initiation phase of therapy. Recent data suggest that polymorphisms in genes encoding several pharmacodynamic determinants of the coagulation cascade may also influence warfarin's antithrombotic dose-response. Of these, VKORC1 polymorphisms account for a significant proportion of the inter-individual variability in warfarin dose requirements in all populations evaluated. Collectively, these data suggest that assessment of genetic polymorphisms affecting both warfarin pharmacokinetics and pharmacodynamics could help to predict warfarin dose requirements in patients. Therefore, the promise of pharmacogenomic-guided dosing as a useful strategy to improve clinical outcomes with warfarin therapy appears credible and warrants further investigation.     

Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

AIM: The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status. METHODS: This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported. RESULTS: INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167-210) ml h(-1), 200 (173-227) ml h(-1) and 201 (171-231) ml h(-1), respectively. The respective apparent clearances of R-warfarin were 127 (106-149) ml h(-1), 126 (111-141) ml h(-1) and 131 (106-156) ml h(-1). The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.98-1.21) and for R-warfarin was 1.00 (0.93-1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC(0-168) of INR was 0.93 (0.81-1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.97-1.13) and for R-warfarin was 1.02 (0.95-1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC(0-168) of INR was 1.01 (0.93-1.15) when coadministered with ginger. The mean ratio (90% CI) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85-1.32) for ginkgo treatment, and 1.00 (0.81-1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. CONCLUSIONS: Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.     

Role of pharmacogenomics in the management of traditional and novel oral anticoagulants

Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration-cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotypeguided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available.     

Effect of high-dose cranberry juice on the pharmacodynamics of warfarin in patients

AIM

To determine if high-dose cranberry juice (240 ml twice daily) alters the pharmacodynamic action of warfarin.

METHODS

Ten male patients taking stable doses of warfarin were given cranberry juice at 240 ml twice daily for 7 days. Prothrombin times were drawn at baseline and days 2, 6 and 8 after administration of the juice. Prothrombin times were averaged for each day and mean times were compared from each study day to baseline using repeated measures anova.

RESULTS

There was no statistical difference between mean prothrombin time at baseline and any day tested during juice administration.

CONCLUSIONS

Cranberry juice (240 ml twice daily for 1 week) did not alter the pharmacodynamics of warfarin in patients.     

Herb-drug interactions: a literature review

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations.Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine).In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.     

Pharmacokinetic interactions of drugs with St John's wort

There is a worldwide increasing use of herbs which are often administered in combination with therapeutic drugs, raising the potential for herb-drug interactions. St John's wort (Hypericum perforatum) is one of the most commonly used herbal antidepressants. A literature search was performed using Medline (via Pubmed), Biological Abstracts, Cochrane Library, AMED, PsycINFO and Embase (all from their inception to September 2003) to identify known drug interaction with St John's wort. The available data indicate that St John's wort is a potent inducer of CYP 3A4 and P-glycoprotein (PgP), although it may inhibit or induce other CYPs, depending on the dose, route and duration of administration. Data from human studies and case reports indicate that St John's wort decreased the blood concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, methadone, midazolam, nevirapine, phenprocoumon, simvastatin, tacrolimus, theophylline and warfarin, whereas it did not alter the pharmacokinetics of carbamazepine, dextromethorphan, mycophenolic acid and pravastatin. St John's wort decreased the plasma concentration of the active metabolite SN-38 in cancer patients receiving irinotecan treatment. St John's wort did not alter the pharmacokinetics of tolbutamide, but increased the incidence of hypoglycaemia. Several cases have been reported that St John's wort decreased cyclosporine blood concentration leading to organ rejection. St John's wort caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when coadministered with selective serotonin-reuptake inhibitors (e.g. sertaline and paroxetine). Both pharmacokinetic and pharmacodynamic components may play a role in these interactions. Because the potential interaction of St John's wort with other drugs is a major safety concern, additional systematic research on herb-drug interactions and appropriate regulation in herbal safety and efficacy is needed.     

<Emphasis Type="Italic">VKORC1</Emphasis> and <Emphasis Type="Italic">CYP2C9</Emphasis> polymorphisms are associated with warfarin dose requirements in Turkish patients

OBJECTIVES: The objective of this study was to determine the quantitative influence of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP 2C9) polymorphisms on warfarin dose requirements in Turkish patients. METHODS: A total of 205 patients taking warfarin for >2 months were enrolled in the study. Deoxyribonucleic acid (DNA) samples from these patients were genotyped for polymorphisms in VKORC1 and CYP2C9 genes. A linear regression analysis was used to determine the independent effects of genetic and non-genetic factors on mean warfarin dose requirements. RESULTS: The VKORC1 promoter polymorphism (3673 G>A) was associated with differences in weekly mean varfarin dose: for GG genotype the dose was 43.18 mg/week, for GA genotype 33.78 mg/week and for AA genoype 25.83 mg/week (P < 0.0001). Patients who carried VKORC1 and CYP2C9 variants needed a 40% lower mean weekly warfarin dose compared to wild types. Variables associated with lower warfarin dose requirements were VKORC1 3673 AA or GA genotype (both P < 0.0001), one or two CYP2C9 variant alleles (both P < 0.0001), increasing age (P < 0.0001) and non-indication of venous thromboembolism for warfarin therapy (P = 0.002). CONCLUSION: Polymorphisms in VKORC1 and CYP2C9 genes were important determinants of warfarin dose requirements in Turkish patients.     

Herb-drug interactions and mechanistic and clinical considerations

Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.     

Evaluation of metabolism-mediated herb-drug interactions

As the use of herbal medicines increases, the public health consequences of drug-herb interactions are becoming more significant. Herbal medicines share the same drug metabolizing enzymes and drug transporters, including cytochrome P450 enzymes (CYPs), glucuronosyltransferases (UGTs), and P-glycoprotein, with several clinically important drugs. Interactions of several commonly used herbal medicines, such as Ginko biloba, milk thistle, and St. John’s wort, with therapeutic drugs including warfarin, midazolam, alprazolam, indinavir, saquinavir, digoxin, nifedipine, cyclosporine, tacrolimus, irinotecan, and imatinib in humans have been reported. Many of these drugs have very narrow therapeutic indices. As the herb-drug interactions can significantly alter pharmacokinetic and pharmacodynamic properties of administered drugs, the drugs interacting with herbal medicines should be identified by appropriate in vitro and in vivo methods. A good understanding of the mechanisms of herb-drug interactions is also essential for assessing and minimizing clinical risks. In vitro methods are useful for providing mechanistic information and evaluating multiple components in herbal medicines. This review describes major factors affecting the metabolism of herbal medicines, mechanisms of herb-drug interactions mediated by CYPs and UGTs, and several in vitro methods to assess the herb-drug interactions. Finally, drug interactions of Ginkgo biloba and St. John’s wort, as representative herbal medicines, are described.