Seville orange juice‐felodipine interaction: Comparison with dilute grapefruit juice and involvement of furocoumarins

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109875/1/cptclpt20013.pd

Cytochrome P450 3A4 and P‐glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109878/1/cptclpt2002114.pd

Influence of Dietary Substances on Intestinal Drug Metabolism and Transport

Successful delivery of promising new chemical entities via the oral route is rife with challenges, some of which cannot be explained or foreseen during drug development. Further complicating an already multifaceted problem is the obvious, yet often overlooked, effect of dietary substances on drug disposition and response. Some dietary substances, particularly fruit juices, have been shown to inhibit biochemical processes in the intestine, leading to altered pharmacokinetic (PK), and potentially pharmacodynamic (PD), outcomes. Inhibition of intestinal CYP3A-mediated metabolism is the major mechanism by which fruit juices, including grapefruit juice, enhances systemic exposure to new and already marketed drugs. Inhibition of intestinal non-CYP3A enzymes and apically-located transport proteins represent recently identified mechanisms that can alter PK and PD. Several fruit juices have been shown to inhibit these processes in vitro, but some interactions have not translated to the clinic. The lack of in vitro-in vivo concordance is due largely to a lack of rigorous methods to elucidate causative ingredients prior to clinical testing. Identification of specific components and underlying mechanisms is challenging, as dietary substances frequently contain multiple, often unknown, bioactive ingredients that vary in composition and bioactivity. A translational research approach, combining expertise from clinical pharmacologists and natural products chemists, is needed to develop robust models describing PK/PD relationships between a given dietary substance and drug of interest. Validation of these models through well-designed clinical trials would facilitate development of common practice guidelines for managing drug-dietary substance interactions appropriately

Student, instructor, and observer agreement regarding frequencies of scientific teaching practices using the Measurement Instrument for Scientific Teaching-Observable (MISTO)

Background: The Scientific Teaching (ST) pedagogical framework encompasses many of the best practices recommended in the literature and highlighted in national reports. Understanding the growth and impact of ST requires instruments to accurately measure the extent to which practitioners implement ST in their courses. Researchers have typically relied on students, instructors, or observers to document course teaching practices, but it remains unclear whether and how these perspectives differ from each other. To address this issue, we modified our previously published instrument to generate the Measurement Instrument for Scientific Teaching-Observable (MISTO), which can be completed by students, instructors, and observers, and we investigated the degree of similarity between these three perspectives across 70 undergraduate science courses at seven different institutions in the USA. Results: We found that the full MISTO and Active Learning subcategory scores showed the highest correlations among the three perspectives, but the degree of correlation between perspectives varied for the other subcategories. Match scores between students and instructors were significantly higher than observer matches for the full MISTO and for the Active Learning, Inclusivity, and Responsiveness subcategories. Conclusions: We find that the level and type of agreement between perspectives varies across MISTO subcategories and that this variation likely stems from intrinsic differences in the course access and scoring decisions of the three perspectives. Building on this data, we recommend MISTO users consider their research goals, available resources, and potential artifacts that may arise when deciding which perspective best fits their needs in measuring classroom teaching practices

Developing User Personas to Aid in the Design of a User-Centered Natural Product-Drug Interaction Information Resource for Researchers

Pharmacokinetic interactions between natural products and conventional drugs can adversely impact patient outcomes. These complex interactions present unique challenges that require clear communication to researchers. We are creating a public information portal to facilitate researchers’ access to credible evidence about these interactions. As part of a user-centered design process, three types of intended researchers were surveyed: drug-drug interaction scientists, clinical pharmacists, and drug compendium editors. Of the 23 invited researchers, 17 completed the survey. The researchers suggested a number of specific requirements for a natural product-drug interaction information resource, including specific information about a given interaction, the potential to cause adverse effects, and the clinical importance. Results were used to develop user personas that provided the development team with a concise and memorable way to represent information needs of the three main researcher types and a common basis for communicating the design’s rationale

Pharmacology of DB844, an Orally Active aza Analogue of Pafuramidine, in a Monkey Model of Second Stage Human African Trypanosomiasis

Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-y​l]-nicotinamide(DB820), exhibiting plasma Cmax values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible.This investigation received financial support from the Bill and Melinda Gates Foundation through the Consortium for Parasitic Drug Development

A Modified Grapefruit Juice Eliminates Two Compound Classes as Major Mediators of the Grapefruit Juice-Fexofenadine Interaction: An In Vitro-In Vivo “Connect”: The Journal of Clinical Pharmacology

The grapefruit juice-fexofenadine interaction involves inhibition of intestinal organic anion transporting polypeptide (OATP)-mediated uptake. Only naringin has been shown clinically to inhibit intestinal OATP; other constituents have not been evaluated. The effects of a modified grapefruit juice devoid of furanocoumarins (~99%) and polymethoxyflavones (~90%) on fexofenadine disposition were compared to effects of the original juice. Extracts of both juices inhibited estrone 3-sulfate and fexofenadine uptake by similar extents in OATP-transfected cells (~50% and ~25%, respectively). Healthy volunteers (n=18) were administered fexofenadine (120 mg) with water, grapefruit juice, or modified grapefruit juice (240 ml) by randomized, three-way crossover design. Compared to water, both juices decreased fexofenadine geometric mean AUC and Cmax by ~25% (p≤0.008 and p≤0.011, respectively), with no effect on terminal half-life (p=0.11). Similar effects by both juices on fexofenadine pharmacokinetics indicate furanocoumarins and polymethoxyflavones are not major mediators of the grapefruit juice-fexofenadine interaction

Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors <em>in vitro</em>

Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD(+) as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.</p

Enhanced Bioactivity of silybin B methylation Products

Abstract: Flavonolignans from milk thistle (Silybum marianum) have been investigated for their cellular modulatory properties, including cancer chemoprevention and hepatoprotection, as an extract (silymarin), as partially purified mixtures (silibinin and isosilibinin), and as pure compounds (a series of seven isomers). One challenge with the use of these compounds in vivo is their relatively short half-life due to conjugation, particularly glucuronidation. In an attempt to generate analogues with improved in vivo properties, particularly reduced metabolic liability, a semi-synthetic series was prepared in which the hydroxy groups of silybin B were alkylated. A total of five methylated analogues of silybin B were synthesized using standard alkylation conditions (dimethyl sulfate and potassium carbonate in acetone), purified using preparative HPLC, and elucidated via spectroscopy and spectrometry. Of the five, one was monomethylated (3), one was dimethylated (4), two were trimethylated (2 and 6), and one was tetramethylated (5). The relative potency of all compounds was determined in a 72 h growth-inhibition assay against a panel of three prostate cancer cell lines (DU-145, PC-3, and LNCaP) and a human hepatoma cell line (Huh7.5.1) and compared to natural silybin B. Compounds also were evaluated for inhibition of both cytochrome P450 2C9 (CYP2C9) activity in human liver microsomes and hepatitis C virus infection in Huh7.5.1 cells. The monomethyl and dimethyl analogues were shown to have enhanced activity in terms of cytotoxicity, CYP2C9 inhibitory potency, and antiviral activity (up to 6-fold increased potency) compared to the parent compound, silybin B. In total, these data suggested that methylation of flavonolignans can increase bioactivity. Graphical Abstract

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group