Wangqing Chen

Pharmacogenetics of drugs withdrawn from the market

The safety and efficacy of candidate compounds are critical factors during the development of drugs, and most drugs have been withdrawn from the market owing to severe adverse reactions. Individuals/populations with different genetic backgrounds may show significant differences in drug metabolism and efficacy, which can sometimes manifest as severe adverse drug reactions. With an emphasis on the mechanisms underlying abnormal drug effects caused by genetic mutations, pharmacogenetic studies may enhance the safety and effectiveness of drug use, provide more comprehensive delineations of the scope of usage, and change the fates of drugs withdrawn from the market.

Inhibition of the organic anion‐transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment

AIM To investigate the effect of quercetin on organic anion transporting polypeptide 1B1 (OATP1B1) activities in vitro and on the pharmacokinetics of pravastatin, a typical substrate for OATP1B1 in healthy Chinese-Han male subjects. METHODS Using human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1, we observed the effect of quercetin on OATP1B1-mediated uptake of estrone-3-sulphate (E3S) and pravastatin. The influence of quercetin on the pharmacokinetics of pravastatin was measured in 16 healthy Chinese-Han male volunteers receiving a single dose of pravastatin (40 mg orally) after co-administration of placebo or 500 mg quercetin capsules (once daily orally for 14 days). RESULTS Quercetin competitively inhibited OATP1B1-mediated E3S uptake with a K(i) value of 17.9 ± 4.6 µm and also inhibited OATP1B1-mediated pravastatin uptake in a concentration dependent manner (IC(50) , 15.9 ± 1.4 µm). In healthy Chinese-Han male subjects, quercetin increased the pravastatin area under the plasma concentration - time curve (AUC(0,10 h) and the peak plasma drug concentration (C(max)) to 24% (95% CI 15, 32%, P < 0.001) and 31% (95% CI 20, 42%, P < 0.001), respectively. After administration of quercetin, the elimination half-life (t(1/2) ) of pravastatin was prolonged by 14% (95% CI 4, 24%, P = 0.027), with no change in the time to reach C(max) (t(max) ). Moreover, quercetin decreased the apparent clearance (CL/F) of pravastatin by 18% (95% CI 75, 89%, P < 0.001). CONCLUSIONS These findings suggest that quercetin inhibits the OATP1B1-mediated transport of E3S and pravastatin in vitro and also has a modest inhibitory influence on the pharmacokinetics of pravastatin in healthy Chinese-Han male volunteers. The effects of quercetin on other OATP1B1 substrate drugs deserve further investigation.

Effects of natural products on the function of human organic anion transporting polypeptide 1B1

In this study, the effects of 136 naturally occurring products, which have been reported to play important roles in modification of Cytochrome P450 (CYP450) activities, on the uptake of estrone-3-sulfate (E3S), a typical OATP1B1 substrate, were evaluated using human embryonic kidney 293 cells stably expressing OATP1B1. At a concentration of 100 μM, 42 natural products inhibited OATP1B1-mediated [3H]E3S uptake by more than 50%, and five of them significantly inhibited OATP1B1-mediated [3H]E3S by more than 80% with the following rank order of potency: quercetin > astragaloside IV > icariin > glycyrrhizic acid > ginsenoside Rc. Inhibitory effects of these natural products on OATP1B1 activity were in a concentration-dependent manner. 11 natural compounds were found exhibiting greater than 50% inhibition at 30 μM with IC50 values ranging from 14.6 ± 3.3 to 28.5 ± 3.0 μM. In conclusion, our data suggest that modification of OATP1B1 transport activity by these natural occurring products may be a mechanism for natural product–drug interactions in humans.

The Pregnane X Receptor Agonist St John’s Wort Has No Effects on the Pharmacokinetics and Pharmacodynamics of Repaglinide

AbstractBackground 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 1mg 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 (Cmax) or the elimination half-life (t½) 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.

Influence of component 5a receptor 1 (C5AR1) −1330T/G polymorphism on nonsedating H1-antihistamines therapy in Chinese patients with chronic spontaneous urticaria

BACKGROUND The nonsedating H1-antihistamines are the first-line medicines for chronic spontaneous urticaria (CSU) patients. However, not all these patients respond well to the antihistamines, and the mechanisms underlying the interindividual differences are still unclear. C5AR1 gene encodes the component 5a receptor (C5aR) protein, which has been reported to play an important role in chronic spontaneous urticaria. OBJECTIVE This study aimed to investigate whether the single nucleotide polymorphisms (SNPs) in C5AR1 are associated with CSU susceptibility and antihistamines therapeutic efficacy in Chinese CSU patients. METHODS A total of 191 CSU patients and 102 healthy controls were prospectively studied in our study. CSU patients were treated by nonsedating H1-antihistamines monotherapy for 4 weeks. The C5AR1 -1330T/G (rs11673309) genotype was determined by Sequenom Massarray. RESULTS Among these 191 CSU patients, there were 114 patients who were treated with desloratadine, 65 were treated with mizolastine, and 12 with fexofenadine. The-1330T alleles in CSU patients were significantly higher than controls (0.555 vs. 0.466, P=0.040, OR=1.429 [1.016-2.010]). The poorest response to desloratadine was observed in heterozygotes, when compared with either GG or TT homozgote (P=0.001). However, there was no significant difference in three genotypes when treated with mizolastine group (P=0.215). CONCLUSION We concluded that the C5AR1 SNP -1330T/G may serve as a useful pharmacodynamic predictor of nonsedating H1-antihistamines efficacy in CSU patients, and -1330T alleles may be taken as a risk factor for the CSU.

Analysis of Long Non-Coding RNA Expression of Lymphatic Endothelial Cells in Response to Type 2 Diabetes

Background: Recent evidence has indicated that long non-coding RNA (lncRNA) is involved in the pathogenesis of type 2 diabetes, but nothing is known about lncRNA expression changes of lymphatic endothelial cells in response to type 2 diabetes. Methods: The GSE38396 dataset was downloaded from the Gene Expression Omnibus database and the probe sets of Human Gnome U133 Plus2.0 microarray were annotated for lncRNA. Differentially expressed lncRNAs between diabetic and non-diabetic lymphatic endothelial cells were calculated. Results: Compared with lymphatic endothelial cells in non-diabetic patients, 31 lncRNAs were down-regulated and 79 lncRNAs were up-regualted in lymphatic endothelial cells of type 2 diabetic patients. Several known lncRNAs were found, such as H19, GAS5, UCA1, CRNDE, GAS5, and LINC00312. Co-expression network of differentially expressed lncRNAs and mRNAs were constructed. Based on genomic regions of these lncRNAs, we found that binding sites of MAF and TCF3 were enriched and these lncRNAs may be related to insulin reporter signaling pathway and response to insulin stimulus. Conclusions: In a word, we found a set of lncRNAs were differentially expressed in lymphatic endothelial cells in response to type 2 diabetes and these lncRNAs may be involved in the pathogenesis of diabetes-related complications.

Polymorphism of ORM1 is associated with the pharmacokinetics of telmisartan.

Background The pharmacokinetics (PKs) and pharmacodynamics (PDs) of telmisartan varies among the individuals, and the main causes remain unknown. The aim of this study was to evaluate the impact of ORM1, as well as ABCC2, ABCB1, ABCG2 and SLCO1B3 polymorphisms, on the disposition of the drug and BP change after taking 40 mg telmisartan in 48 healthy Chinese males. Method A total of 48 healthy males were included in this trial. Every volunteer ingested a single dose of 40 mg telmisartan, and the plasma drug concentration and blood pressure (BP) were measured up to 48 h. Result In this study, the area under the plasma concentration-time curve (AUC) in the heterozygotes of ORM1 113AG was higher than that in the wild-type homozygotes, AUC(0–48) (113AA vs. 113AG, 1,549.18±859.84 ng·h/ml vs. 2,313.54±1,257.71 ng·h/ml, P = 0.033), AUC(0–∞) (113AA vs. 113AG, 1,753.13±1,060.60 ng·h/ml vs. 2,686.90±1,401.87 ng·h/ml, P = 0.016), and the change(%) of the diastolic blood pressure (DBP) from the baseline BP value also showed a significant difference between the ORM1 113AG and 113AA genotypes at 5 h after taking telmisartan (P = 0.026). This study also showed that the allele of ABCC2 C3972T would affected the disposition of telmsiartan and the DBP change significantly after taking the drug. However, the common SNPs of ABCG2 C421, ABCB1 C3435T, and SLCO1B3 T334G showed no impacts on the PKs of telmisartan or BP change(%) in our trial. Conclusion The ORM1 A113G polymorphism was associated with the PKs variability after taking telmsiartan, as well as ABCC2 C3972T. The heterozygotes of ORM1 113AG showed a larger AUC and a notable BP change(%) from the baseline compared with the wild-type. Trial Registration Chinese Clinical Trial Registry ChiCTR-TNC-10000898

The expression of mCTLA-4 in skin lesion inversely correlates with the severity of psoriasis

BACKGROUND Psoriasis is a chronic inflammatory disease characterized by epidermal hyperplasia and increased T cell infiltration. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key factor that affects T cell function and immune response. However, whether the expression of CTLA-4 affects the severity of psoriasis is still unknown. OBJECTIVE The aim of the project was to investigate the correlation between the expression of CTLA-4 and the severity of psoriasis. METHODS The plasma soluble CTLA-4 levels and membrane CTLA-4 expression were measured by enzyme-linked immunosorbent assay and immunohistochemistry analysis in mild, moderate and severe psoriasis patients, respectively. Imiquimod-induced mouse model of psoriasis was treated with CTLA-4 immunoglobulin fusion protein (CTLA-4 Ig) or anti-CTLA-4 antibody. Epidermal thickness and infiltrating CD3+ T cell counts were evaluated. RESULTS The plasma soluble CTLA-4 levels had no significant difference among mild, moderate, and severe patients (p > 0.05). However, the membrane CTLA-4 expression in skin was significantly higher in mild psoriasis patients compared to moderate and severe psoriasis patients (17652.86 ± 18095.66 vs 6901.36 ± 4400.77 vs 3970.24 ± 5509.15, p < 0.001). Furthermore, in imiquimod-induced mouse model of psoriasis, the results showed that mimicking CTLA-4 function improved the skin phenotype and reduced epidermal thickness (172.87 ± 28.25 vs 245.87 ± 36.61 μm, n = 6, p < 0.01) as well as infiltrating CD3+ T cell counts (5.09 ± 3.45 vs 13.45 ± 4.70, p < 0.01) compared to control group. However, blocking CTLA-4 function aggregated the skin phenotype including enhanced epidermal thickness and infiltrating CD3+ T cell counts compared to control group. CONCLUSION These results indicated that the expression of mCTLA-4 in skin lesion inversely correlated with the severity of psoriasis and CTLA-4 might play a critical role in the disease severity of psoriasis.

Whole Exome Sequencing in Psoriasis Patients Contributes to Studies of Acitretin Treatment Difference

Psoriasis vulgaris is an immune-mediated inflammatory skin disease. Although acitretin is a widely used synthetic retinoid for moderate to severe psoriasis, little is known about patients’ genetics in response to this drug. In this study, 179 patients were enrolled in either the discovery set (13 patients) or replication set (166 patients). The discovery set was sequenced by whole exome sequencing and sequential validation was conducted in the replication set by MassArray assays. Four SNPs (single nucleotide polymorphisms) (rs1105223T>C in CRB2, rs11086065A>G in ANKLE1, rs3821414T>C in ARHGEF3, rs1802073 T>G in SFRP4) were found to be significantly associated with acitretin response in either co-dominant or dominant models via multivariable logistic regression analysis, while CRB2 rs1105223CC (OR = 4.10, 95% CI = 1.46–11.5, p = 0.007) and ANKLE1 rs11086065AG/GG (OR = 2.76, 95% CI = 1.42–5.37, p = 0.003) were associated with no response to acitretin after 8-week treatment. Meanwhile, ARHGEF3 rs3821414CT/CC (OR = 0.25, 95% CI = 0.10–0.68, p = 0.006) and SFRP4 rs1802073GG/GT (OR = 2.40, 95% CI, 1.23–4.70, p = 0.011) were associated with a higher response rate. Four new genetic variations with potential influences on the response to acitretin were found in this study which may serve as genetic markers for acitretin in psoriasis patients.

Frizzled-related proteins 4 (SFRP4) rs1802073G allele predicts the elevated serum lipid levels during acitretin treatment in psoriatic patients from Hunan, China

Background Acitretin is a second-generation synthetic retinoid, and is widely used for treating the severe psoriasis vulgaris. However, it should be chosen with caution for its cardiovascular risk, and it is reported that acitretin may increase the serum lipids. The purpose of this study is to investigate the relationship between the Frizzled-related proteins 4 (SFRP4) rs1802073 polymorphism and the changes of serum lipids in Chinese psoriatic patients during the treatment with acitretin. Methods In our study, 100 psoriatic patients were recruited systematically treated with acitretin (30 mg/day) for at least eight weeks. Data of the patients’ demographic and clinical characteristics and the results of serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were collected pre- and post-treatment. Results A total of 84 psoriatic patients were enrolled and divided into three groups by SFRP4 rs1802073 genotypes. The patients who carried with TT genotype had maintained levels of TG and LDL-C after acitretin treatment, while patients with GG/GT genotypes had significantly elevated levels of serum TG and LDL-C compared to the TT genotype (ΔTG%: 27.53 ± 59.13 vs −1.47 ± 37.79, p = 0.026, ΔLDL-C%: 10.62 ± 26.57 vs −1.29 ± 17.07, p = 0.042). The association of rs1802073 with TG and LDL-C profiles remained significant after adjusting for age, gender, and body mass index. Although without significance, the pre-post change in serum level of TC across rs1802073 GG/GT genotypes demonstrated a trend similar to TG and LDL, and the serum level of HDL-C demonstrated a trend opposite to TG, TC and LDL. Conclusions Our results demonstrated that SFRP4 rs1802073 polymorphism was found to be associated with elevated serum lipid levels after acitretin treatment, and it may serve as a genetic marker of safe and precise treatment for individual psoriatic patients.