Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018)

Introduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.

Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.

Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted.     

三磷酸腺苷结合盒运转体A1与颈动脉粥样硬化斑块的关系

目的 探讨三磷酸腺苷结合盒运转体A1(ATP binding cassette transporter A1,ABCA1)在人颈动脉粥样硬化斑块中的表达变化及作用机制.方法 收集24例人颈动脉粥样硬化斑块标本和10例肠系膜动脉标本(对照组),采用RT-PCR测定ABCA1 mRNA和视黄酸X受体α(RXRα)mRNA表达水平,并采用Western Blot检测ABCA1及RXRα的蛋白表达水平.24例人颈动脉粥样硬化斑块标本按病理分级,比较病理组织为Ⅲ级和Ⅰ级动脉粥样硬化组织间ABCA1 mRNA、RXRαmRNA表达水平及蛋白表达水平.结果 颈动脉粥样硬化斑块组的ABCA1 mRNA(0.79±0.04)和RXRα mRNA(0.73±0.04)表达与对照组相比上调,差异有统计学意义(P＜0.05);ABCA1 mRNA与RXRα mRNA增加水平相关(P＜0.05);颈动脉粥样硬化斑块的ABCA1蛋白表达(0.22±0.03)下调水平与对照组(0.53±0.03)相比差异有统计学意义(P＜0.05);Ⅲ级和Ⅰ级动脉硬化斑块ABCA1mRNA、RXRα mRNA及蛋白表达水平差异有统计学意义(P＜0.05).结论 ABCA1及RXRα蛋白表达水平下调可能是进展性动脉粥样硬化损害的关键因素.     

Effect of age and caloric restriction on insulin receptor binding and glucose transporter levels in aging rats

We report on the effect of age and chronic caloric restriction (CR) on insulin binding and glucose transporter content in both diaphragm and heart muscle membrane of young (11 months), mid-age (17 months), and old (29 month) ad libitum fed and CR Brown-Norway rats. The control animals received rat chow ad lib and CR animals were allowed 60% of ad libitum food. The CR regimen was initiated at four months of age and the animals were maintained on their respective diets until necropsy. There was no effect of age on insulin binding for either ad libitum or CR animals at each age evaluated. Caloric restriction significantly lowered insulin levels at each age studied when compared to the ad libitum-fed rats. However, CR animals were noted to have increased insulin binding (p < 0.001) compared to ad libitum-fed animals at each age for diaphragm muscle. For the heart, there appeared to be a decreased binding, particularly at higher insulin concentrations, in CR-fed animals. There was no net change in Glut-1 or Glut-4 levels for heart muscle membrane, or Glut-4 levels for diaphragm muscle membrane between ad libitum or CR animals. This data indicates that caloric restriction may have tissue-specific effects for insulin receptor binding, and that the improved insulin sensitivity in CR states is not a result of altered glucose transporter protein content.     

运动性中枢疲劳及乳酸对大鼠大脑皮质神经细胞MCT mRNA表达的影响

目的:探讨运动性中枢疲劳时大鼠大脑皮质MCT1、MCT2mRNA表达的变化以及乳酸对大鼠大脑皮质神经元MCT2mRNA表达的影响。方法:12只Wistar大鼠随机分为对照组和力竭训练1周组,每组6只。通过7天力竭训练建立中枢疲劳模型,观察中枢疲劳时大鼠大脑皮质MCT1、MCT2mR-NA表达变化;采用原代培养的大鼠大脑皮质神经元,观察不同浓度乳酸作用后大鼠大脑皮质神经元MCT2mRNA表达的变化。采用Trizol法提取大脑皮质和神经元总RNA;用SYBRAgreenI荧光定量RT-PCR测定MCT1及MCT2mRNA表达变化。结果:整体水平:力竭训练1周组MCT1mRNA表达无明显变化,而MCT2mRNA表达较对照组显著升高6·35±3·54倍(P<0·05)。细胞水平:乳酸作用后,神经元MCT2mRNA表达在pH=7·25时较对照组(pH=7·35组)升高3·08±2·38倍(P<0·05)。但随着乳酸浓度进一步升高,MCT2mRNA表达无明显增加。结果提示,中枢疲劳可能引发大脑皮质神经元MCT2mRNA表达升高,MCT2基因表达可能与乳酸在中枢疲劳中的作用有关。     

Membrane Transporters in Drug Disposition

Many clinically used drugs and their metabolites as well as a variety of environmental toxins are organic cations at physiologic pH. Secretion in the renal proximal tubule constitutes a major pathway in the elimination of organic cations. In this report, the results of studies recently performed in this laboratory are presented. First, the molecular cloning of a novel splice variant of organic cation transporter from rat kidney (rOCTIA) is described. The functional characteristics of the transporter are discussed along with the implications of RNA splicing in enhancing transporter diversity. Second, the molecular cloning of the first human organic cation transporter (hOCTI) is described. Distinct interspecies differences in the tissue distribution and function of this transporter is presented. These studies have paved the way for elucidating molecular structure function relationships of organic cation transporters and for determining their physiologic role in drug absorption and elimination. The cloned transporters can be used in mammalian expression systems for screening candidate compounds identified during drug discovery and development and in the in vivo prediction of the pharmacokinetics of therapeutic agents.     

Ontogenetic profile of glutamate uptake in brain structures slices from rats: sensitivity to guanosine

The excitotoxicity of the neurotransmitter glutamate has been shown to be connected with many acute and chronic diseases of the CNS. High affinity sodium-dependent glutamate transporters play a key role in maintaining adequate levels of extracellular glutamate. In the present study, we used slices of striatum, hippocampus and cortex from rat brain to describe the in vitro profile of glutamate uptake during development and ageing, and its sensitivity to guanosine. In all structures, glutamate uptake was higher in immature animals. There was a maximum decrease in glutamate uptake in striatum and hippocampus in 15-month-old rats, which later increased, while in cortex there was a significant decrease in rats aged 60 days old. The effect of guanosine seems to be age and structure dependent since the increase in basal glutamate uptake was only seen in slices of cortex from 10-day-old animals.     

载脂蛋白A-Ⅰ对三磷酸腺苷结合盒转运体A1的影响

目的：以THP-1巨噬细胞源性泡沫细胞为研究对象，观察载脂蛋白A-I对THP-1巨噬细胞源性泡沫细胞胆固醇流出和三磷酸腺苷结合盒转运体A1(ABCA1)的影响,从而探讨载脂蛋白A-I对动脉粥样硬化(As)发生发展的影响。方法:用液体闪烁计数器检测细胞内胆固醇流出, 高效液相色谱分析细胞内总胆固醇、游离胆固醇和胆固醇酯含量, 运用逆转录-多聚酶链反应和Western 印迹分别检测ABCA1 mRNA 与ABCA1蛋白的表达,用流式细胞术检测细胞平均ABCA1荧光强度。 结果:载脂蛋白A-I引起THP-1巨噬细胞源性泡沫细胞总胆固醇、游离胆固醇与胆固醇酯呈时间依赖性减少, 而ABCA1蛋白质水平、细胞平均ABCA1荧光强度以及细胞内胆固醇流出呈时间依赖性增加,但ABCA1 mRNA没有明显变化。巯基蛋白酶抑制剂(leupeptin 和ALLN)增加ABCA1蛋白质水平,而其它蛋白酶抑制剂(pepstatin A、aprotinin及phosphoramiddon)不增加ABCA1蛋白质水平,蛋白体抑制剂(lactacytin)和溶酶体抑制剂(NH4Cl)也不影响ABCA1蛋白质水平。 结论:巯基蛋白酶可降解THP-1巨噬细胞源性泡沫细胞ABCA1蛋白质,而载脂蛋白A-I可阻碍巯基蛋白酶降解ABCA1蛋白质,从而提高THP-1巨噬细胞源性泡沫细胞ABCA1 蛋白质水平, 增加细胞内胆固醇流出, 降低细胞内胆固醇聚积。     

Changes in the infectivity, pyruvate kinase activity, acid phosphatase activity and P-glycoprotein expression in glibenclamide-resistant Leishmania mexicana

We previously demonstrated susceptibility of Leishmania sp. to glibenclamide, a K⁺-ATP transport blocker which interacts with members of the superfamily of adenosine 5′ triphosphate-binding cassette transporters. In order to characterize the molecular differences between a sensitive Leishmania strain, NR(Gs), and an experimentally selected glibenclamide-resistant strain, NR(Gr), specific biochemical and functional parameters have been evaluated both in the wild type and in the resistant strain. Most noteworthy, NR(Gr) exhibit an increased expression of P-glycoprotein and a decreased activity of functional key enzymes such as acid phosphatase, a prominent virulent factor of the parasite, and pyruvate kinase, a key control enzyme for both carbohydrate and protein metabolism. The specific biochemical, metabolic and functional changes observed in the resistant strain correlated with a reduced infectivity of stationary phase NR(Gr) in J774 macrophages and suggested a mechanism to overcome the effect of glibenclamide. Received: 21 January 2000 / Accepted: 1 March 2000