Constitutive activation of nuclear factor‐E2‐related factor 2 induces biotransformation enzyme and transporter expression in livers of mice with hepatocyte‐specific deletion of Kelch‐like ECH‐associated protein 1

Chemicals that activate nuclear factor‐E2‐related factor 2 (Nrf2) often increase multidrug‐resistance‐associated protein (Mrp) expression in liver. Hepatocyte‐specific deletion of Kelch‐like ECH‐associated protein 1 (Keap1) activates Nrf2. Use of hepatocyte‐specific Keap1 deletion represents a nonpharmacological method to determine whether constitutive Nrf2 activation upregulates liver transporter expression in vivo. The mRNA, protein expression, and localization of several biotransformation and transporters were determined in livers of wild‐type and hepatocyte‐specific Keap1‐null mice. Sulfotransferase 2a1/2, NADP(H):quinone oxidoreductase 1, cytochrome P450 2b10, 3a11, and glutamate–cysteine ligase catalytic subunit expression were increased in livers of Keap1‐null mice. Organic anion‐transporting polypeptide 1a1 expression was nearly abolished, as compared to that detected in livers of wild‐type mice. By contrast, Mrp 1–5 mRNA and protein levels were increased in Keap1‐null mouse livers, with Mrp4 expression being more than 15‐fold higher than wild types. In summary, Nrf2 has a significant role in affecting Oatp and Mrp expressions

Numerical modelling of MPA-CVD reactors with the discontinuous Galerkin finite element method

In this article we develop a fully self consistent mathematical model describing the formation of a hydrogen plasma in a microwave power assisted chemical vapour deposition (MPA-CVD) reactor employed for the manufacture of synthetic diamond. The underlying multi-physics model includes constituent equations for the background gas mass average velocity, gas temperature, electromagnetic field energy and plasma density. The proposed mathematical model is numerically approximated based on exploiting the discontinuous Galerkin finite element method. We demonstrate the practical performance of this computational approach on a variety of CVD reactor geometries for a range of operating conditions

A two-way interaction between methotrexate and the gut microbiota of male Sprague Dawley rats

Methotrexate (MTX) is a chemotherapeutic agent that can cause a range of toxic side effects including gastrointestinal damage, hepatotoxicity, myelosuppression, and nephrotoxicity and has potentially complex interactions with the gut microbiome. Following untargeted UPLC-qtof-MS analysis of urine and fecal samples from male Sprague–Dawley rats administered at either 0, 10, 40, or 100 mg/kg of MTX, dose-dependent changes in the endogenous metabolite profiles were detected. Semiquantitative targeted UPLC-MS detected MTX excreted in urine as well as MTX and two metabolites, 2,4-diamino-N-10-methylpteroic acid (DAMPA) and 7-hydroxy-MTX, in the feces. DAMPA is produced by the bacterial enzyme carboxypeptidase glutamate 2 (CPDG2) in the gut. Microbiota profiling (16S rRNA gene amplicon sequencing) of fecal samples showed an increase in the relative abundance of Firmicutes over the Bacteroidetes at low doses of MTX but the reverse at high doses. Firmicutes relative abundance was positively correlated with DAMPA excretion in feces at 48 h, which were both lower at 100 mg/kg compared to that seen at 40 mg/kg. Overall, chronic exposure to MTX appears to induce community and functionality changes in the intestinal microbiota, inducing downstream perturbations in CPDG2 activity, and thus may delay MTX detoxication to DAMPA. This reduction in metabolic clearance might be associated with increased gastrointestinal toxicity

Genetics or environment in drug transport: the case of organic anion transporting polypeptides and adverse drug reactions

Introduction: Organic anion transporting polypeptide (OATP) uptake transporters are important for the disposition of many drugs and perturbed OATP activity can contribute to adverse drug reactions (ADRs). It is well documented that both genetic and environmental factors can alter OATP expression and activity. Genetic factors include single nucleotide polymorphisms (SNPs) that change OATP activity and epigenetic regulation that modify OATP expression levels. SNPs in OATPs contribute to ADRs. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver diseases such as non-alcoholic fatty liver disease, cholestasis and hepatocellular carcinoma change the expression of multiple OATP isoforms. The role of liver diseases in the occurrence of ADRs is unknown. Areas covered: This article covers the roles OATPs play in ADRs when considered in the context of genetic or environmental factors. The reader will gain a greater appreciation for the current evidence regarding the salience and importance of each factor in OATP-mediated ADRs. Expert opinion: A SNP in a single OATP transporter can cause changes in drug pharmacokinetics and contribute to ADRs but, because of overlap in substrate specificities, there is potential for compensatory transport by other OATP isoforms. By contrast, the expression of multiple OATP isoforms is decreased in liver diseases, reducing compensatory transport and thereby increasing the probability of ADRs. To date, most research has focused on the genetic factors in OATP-mediated ADRs while the impact of environmental factors has largely been ignored

Nonalcoholic steatohepatitis in precision medicine: Unraveling the factors that contribute to individual variability

There are numerous factors in individual variability that make the development and implementation of precision medicine a challenge in the clinic. One of the main goals of precision medicine is to identify the correct dose for each individual in order to maximize therapeutic effect and minimize the occurrence of adverse drug reactions. Many promising advances have been made in identifying and understanding how factors such as genetic polymorphisms can influence drug pharmacokinetics (PK) and contribute to variable drug response (VDR), but it is clear that there remain many unidentified variables. Underlying liver diseases such as nonalcoholic steatohepatitis (NASH) alter absorption, distribution, metabolism, and excretion (ADME) processes and must be considered in the implementation of precision medicine. There is still a profound need for clinical investigation into how NASH-associated changes in ADME mediators, such as metabolism enzymes and transporters, affect the pharmacokinetics of individual drugs known to rely on these pathways for elimination. This review summarizes the key PK factors in individual variability and VDR and highlights NASH as an essential underlying factor that must be considered as the development of precision medicine advances. A multifactorial approach to precision medicine that considers the combination of two or more risk factors (e.g. genetics and NASH) will be required in our effort to provide a new era of benefit for patients

Implications of Species Differences in Function and Localization of Transporters at the Blood-Testis Barrier

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