A case of simvastatin-induced myopathy with SLCO1B1 genetic predisposition and co-ingestion of linagliptin and Stevia rebaudiana.

WHAT IS KNOWN AND OBJECTIVE: SLCO1B1 T521>C variant carriers are susceptible to simvastatin-induced myopathy. We report a patient who developed rhabdomyolysis possibly triggered by a drug-drug and/or herb-drug interaction. CASE DESCRIPTION: A 69-year-old man presented with myalgia and weakness progressing to severe rhabdomyolysis. He had been taking 40 mg simvastatin daily for 10 years and recently consumed supplements, including Stevia rebaudiana and linagliptin. Genotyping revealed he carried one copy of SLCO1B1 T521>C and two copies of ABCG2 C421>A. WHAT IS NEW AND CONCLUSION: Despite apparent long-term safe administration, co-ingestion of simvastatin and other CYP3A4 inhibitors may result in severe myopathy in those at increased genetic risk.

Fangjifuling Ameliorates Lipopolysaccharide-Induced Renal Injury via Inhibition of Inflammatory and Apoptotic Response in Mice.

BACKGROUND/AIMS: Acute kidney injury (AKI) is a frequent and serious complication of sepsis; however, there is no effective treatment for it. FangJiFuling (FF) decoction is widely used to treat acute glomerulonephritis and nephritic syndrome in the clinical setting. METHODS: On the basis of its anti-inflammatory properties, the renoprotective effect of FF on a mouse model of lipopolysaccharide (LPS)-induced AKI was investigated. Major compounds were identified in FF with high-performance liquid chromatography. A bioinformatics analysis tool was used to predict target genes. Quantitative real-time PCR and western blot analyses were performed to validate the targets. Furthermore, the expression of a target gene was silenced by small interfering RNA-mediated knockdown in vitro. RESULTS: Bioinformatics analysis indicated that inflammation, apoptosis, and cell junction were closely related to the renoprotective effects of FF. Validation was confirmed by an in vivo test. A reduction of inflammatory cell infiltration and inflammatory cytokine mRNA expression (iNOS, NF-κB, MCP-1, and TNF-α) following the administration of FF (50 mg/kg) was observed in LPS-treated renal tissue. In addition, FF treatment suppressed mitochondrial-mediated apoptosis by regulating the Bax/Bcl-2 ratio in LPS-induced renal injury. Silencing Cx43, a cell-to-cell junction protein, was found to enhance the protective effect of FF against LPS-induced renal injury. CONCLUSION: Our study suggests that FF exhibits a renoprotective effect against LPS-induced inflammatory and apoptotic responses. In addition, Cx43 might be involved in these processes. These findings indicate the potential role of FF as a natural renoprotective product.

Screening Ingredients from Herbs against Pregnane X Receptor in the Study of Inductive Herb-Drug Interactions: Combining Pharmacophore and Docking-Based Rank Aggregation.

The issue of herb-drug interactions has been widely reported. Herbal ingredients can activate nuclear receptors and further induce the gene expression alteration of drug-metabolizing enzyme and/or transporter. Therefore, the herb-drug interaction will happen when the herbs and drugs are coadministered. This kind of interaction is called inductive herb-drug interactions. Pregnane X Receptor (PXR) and drug-metabolizing target genes are involved in most of inductive herb-drug interactions. To predict this kind of herb-drug interaction, the protocol could be simplified to only screen agonists of PXR from herbs because the relations of drugs with their metabolizing enzymes are well studied. Here, a combinational in silico strategy of pharmacophore modelling and docking-based rank aggregation (DRA) was employed to identify PXR's agonists. Firstly, 305 ingredients were screened out from 820 ingredients as candidate agonists of PXR with our pharmacophore model. Secondly, DRA was used to rerank the result of pharmacophore filtering. To validate our prediction, a curated herb-drug interaction database was built, which recorded 380 herb-drug interactions. Finally, among the top 10 herb ingredients from the ranking list, 6 ingredients were reported to involve in herb-drug interactions. The accuracy of our method is higher than other traditional methods. The strategy could be extended to studies on other inductive herb-drug interactions.

Effects of grapefruit juice and SLCO1B1 388A>G polymorphism on the pharmacokinetics of pitavastatin.

Pitavastatin undergoes little hepatic metabolism but it is a substrate for uptake and efflux transporters, particularly OATP1B1 (gene SLCO1B1). A previous study in 8 Japanese healthy subjects showed that co-administration with grapefruit juice (GFJ) resulted in a small increase in systemic exposure to pitavastatin. We examined whether common polymorphisms in SLCO1B1 might influence the pharmacokinetics of pitavastatin or the interaction with GFJ. Twelve Chinese healthy male volunteers took pitavastatin 2 mg orally with water or with GFJ on separate occasions and plasma concentrations of pitavastatin acid and lactone were measured over 48 h. GFJ increased the mean area under the plasma concentration-time curve (AUC0-48 h) for both pitavastatin acid and lactone by 14% (p<0.05). Subjects with SLCO1B1 *1b/*1b haplotype (388GG-521TT) had 47% and 44% higher systemic exposure for pitavastatin acid and lactone than the SLCO1B1 *1a carriers (388AA/AG-521TT, p<0.05 and p=0.005, respectively). The SLCO1B1 388A>G polymorphism, which increases transporter activity for some statins, was associated with higher plasma levels of pitavastatin acid and lactone in subjects with the homozygous variant indicating decreased hepatic uptake. Co-administration of pitavastatin with GFJ resulted in a small but significant increase in plasma levels in healthy Chinese subjects.

Theranostics meets traditional Chinese medicine: rational prediction of drug-herb interactions.

Herbal medicines including traditional Chinese medicine are becoming increasingly more popular worldwide. However, there is considerable potential for interaction between herbal components and drugs, as all herbal medicines contain a combination of potentially biologically active compounds possessing various inherent pharmacological activities, and the components of herbal products consumed are eliminated from the body by the same mechanisms that remove drugs. Indeed, many so-called conventional drugs are derived from plant sources. This article provides an update on the mechanisms and evidence of drug-herb interactions (DHIs) and genetic influences on DHIs. The rational prediction of clinically important DHIs is also discussed. Individualized and targeted drug therapy could be achieved by identifying the population most likely to be helped or harmed by drug-herb coadministration.

Herb-drug interactions: methods to identify potential influence of genetic variations in genes encoding drug metabolizing enzymes and drug transporters.

Herbal supplements are often used concomitantly with conventional medications resulting in considerable potential for herb-drug interactions. These interactions, which are generally through interfering with pharmacokinetic and/or pharmacodynamic pathways, may result in beneficial effects or more often adverse reactions such as toxicity or treatment failure and may be influenced by multiple environmental and/or genetic factors. The pharmacogenetic approach may help to identify some interactions which may be more pronounced or only occur in specific groups of subjects although the complex nature of the herbal medicines may limit the discovery of such an interaction. Preclinical studies such as gene expression profiling in rodent liver may help to define metabolic pathways influenced by herbal medicines and facilitate more accurate targeting of human in vivo studies. This review discusses the mechanisms of herb-drugs interaction and the potential influence of genetic variation on herb-drug interactions based on available clinical evidence.

The pregnane X receptor agonist St John's Wort has no effects on the pharmacokinetics and pharmacodynamics of repaglinide.

BACKGROUND AND OBJECTIVES: St John's wort (SJW; Hypericum perforatum) has been one of the most commonly used herbal remedies for mood disorders. This study aimed to investigate the effect of SJW, a pregnane X receptor (PXR) agonist, on the pharmacokinetics and pharmacodynamics of repaglinide, a widely consumed glucose-lowering drug. METHODS: In a two-phase, randomized, crossover study with a 4-week washout period between phases, 15 healthy subjects with specific solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes were given pretreatment with SJW 325 mg or placebo three times daily for 14 days, and a single dose of repaglinide 1 mg was administered followed by 75 g glucose at 15 minutes after repaglinide administration. RESULTS: In all subjects, SJW had no effect on the total area under the plasma concentration-time curve from time zero to infinity (AUC(∞)), the peak plasma concentration (C(max)) or the elimination half-life (t(½)) of repaglinide. In addition, SJW had no significant effect on the blood glucose-lowering and insulin-elevating effects of repaglinide. CONCLUSION: Consumption of SJW for 14 days had no clinically significant effect on the pharmacokinetics and pharmacodynamics of repaglinide.

Interactions between herbal remedies and medicinal drugs--considerations about Cuba.

The use of herbal products to treat a wide range of conditions is rapidly leading to increased intake of phytochemicals. This is one of the main reasons for reinforcing the surveillance of the safety, efficacy and quality control of traditional and complementary medicines. Herbal preparations can interact with a drug at pharmacokinetic, pharmacodynamic and pharmacogenetic levels. In this article interactions between herbal products and conventional medicines are reviewed. Reports about side effects of traditional medicines and main interactions between herbal medicines and conventional drugs in Cuba are also included. Herbal products are currently not subject to the rigorous testing indispensable for conventional drugs. However, if potential drug interactions are to be predicted, it is essential that the ability of herbal products to interfere with drug-metabolizing enzyme systems is fully established.

Identification and characterization of isoflavonoid specific glycosyltransferase and malonyltransferase from soybean seeds.

Isoflavonoids are a diverse group of biologically active natural products that accumulate in soybean seeds during development. The majority of isoflavonoids are accumulated in the form of their glyco- and malonyl-conjugates in soybean seeds. The conjugation step confers stability and solubility to isoflavone aglycones enabling their compartmentalization to vacuoles or transport to the site of accumulation. A functional genomic approach was used to identify isoflavonoid specific glycosyltransferase (UGT) and malonyltransferase (MT) from soybean (Glycine max) seeds. An expressed sequence tag database for soybean was searched by key words to make a list of candidate genes. The full-length cDNAs for candidate UGTs and MTs were obtained and cloned into an expression vector for the production of recombinant enzymes. The in vitro enzymatic activity assays were conducted for recombinant UGTs and MTs using uridine diphosphate glucose and malonyl CoA, respectively, as donors with isoflavone substrates. Among several recombinant enzymes, UGT73F2 showed glycosylation activity towards all three soybean isoflavone aglycones and GmMT7 exhibited malonylation activity towards isoflavone glycosides. The subcellular localization study revealed both UGT73F2 and GmMT7 to be in the cytoplasm. The transcripts and protein accumulation patterns for UGT73F2 and GmMT7 genes have provided further support for their in planta function.

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.