Current Drug Metabolism - Volume 20, Issue 5, 2019

Background: Acute Kidney Injury (AKI) is a sudden decrease in kidney function. In the early period, the highest percentage of AKI occurs among newborns hospitalized in the neonatal intensive care units, especially premature neonates. The prognosis of AKI depends on the type and severity of the cause of an injury, the accuracy and the time of diagnosis and treatment. The concentration of serum creatinine is still the main diagnostic test, although it changes in the course of AKI later than glomerular filtration rate GFR. In addition, the reliability of the determination of creatinine level is limited because it depends on many factors. New studies have presented other, more useful laboratory markers of renal function that can be measured in serum and/or in urine. Objective: The aim of the work was to present the latest data about tubular and glomerular biomarkers of acute kidney injury in newborns. Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature by using focused review topics. According to the conceptual framework, the main idea of research literature has been summarized and presented in this study. Results: The concentrations of some novel biomarkers are higher in serum and/or urine of term and preterm newborns with AKI, especially in the course of perinatal asphyxia. Conclusion: In this systematic review of the literature, we have highlighted the usefulness of biomarkers in predicting tubular and/or glomerular injury in newborns. However, novel biomarkers need to prove their clinical applicability, accuracy, and cost-effectiveness prior to their implementation in clinical practice.

Background: Radiation is the fourth most prevalent type of pollution following the water, air and noise pollution. It can adversely affect normal bodily functions. Radiation alters the protein and mRNA expression of drugmetabolizing enzymes and drug transporters and the pharmacokinetic characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Therefore, it is important to study the pharmacokinetic changes in drugs under radiation. Methods: To update data on the effects of ionizing radiation and non-ionizing radiation caused by environmental pollution or clinical treatments on the protein and mRNA expression of drug-metabolizing enzymes and drug transporters. Data and information on pharmacokinetic changes in drugs under radiation were analyzed and summarized. Results: The effect of radiation on cytochrome P450 is still a subject of debate. The widespread belief is that higherdose radiation increased the expression of CYP1A1 and CYP1B1 of rat, zebrafish or human, CYP1A2, CYP2B1, and CYP3A1 of rat, and CYP2E1 of mouse or rat, and decreased that of rat’s CYP2C11 and CYP2D1. Radiation increased the expression of multidrug resistance protein, multidrug resistance-associated protein, and breast cancer resistance protein. The metabolism of some drugs, as well as the clearance, increased during concurrent chemoradiation therapy, whereas the half-life, mean residence time, and area under the curve decreased. Changes in the expression of cytochrome P450 and drug transporters were consistent with the changes in the pharmacokinetics of some drugs under radiation. Conclusion: The findings of this review indicated that radiation caused by environmental pollution or clinical treatments can alter the pharmacokinetic characteristics of drugs. Thus, the pharmacokinetics of drugs should be rechecked and the optimal dose should be re-evaluated after radiation.

Background: Evidence has revealed that renal impairment can affect the systemic exposure of drugs which are predominantly eliminated via the liver. The modulation of drug-metabolizing enzymes and transporters expressed in the liver and/or small intestine by diverse entities, including uremic toxins, in systemic circulation of patients with severe renal failure is considered as the cause of atypical pharmacokinetics, which sometimes induce undesirable adverse events that are especially critical for drugs with narrow therapeutic window such as anticancer drugs. A dosing strategy for anticancer drugs in these patients needs to be established. Methods: The effects of renal impairment on the systemic exposure and safety of anticancer drugs were summarized. The proposed mechanisms for the alterations in the pharmacokinetics of these anticancer drugs were also discussed. Results: Changes in pharmacokinetics and clinical response were reported in 9 out of 10 cytotoxic anticancer drugs investigated, although available information was limited and sometimes controversial. Systemic exposure of 3 out of 16 tyrosine kinase inhibitors was higher in patients with severe renal failure than that in patients with normal kidney function. An increase in systemic exposure of anticancer drugs in patients with renal impairment is likely to be observed for substrates of OATP1B1, despite the limited evidence. Conclusion: The molecular basis for the effect of uremia on non-renal drug elimination still needed to be clarified with further studies to generate generalizable concepts, which may provide insights into establishing better clinical usage of anticancer drugs, i.e. identifying patients at risk and dose adjustment.

Background: Sodium Taurocholate Co-transporting Polypeptide (NTCP) and Bile Salt Export Pump (BSEP) play significant roles as membrane transporters because of their presence in the enterohepatic circulation of bile salts. They have emerged as promising drug targets in related liver disease. Methods: We reviewed the literature published over the last 20 years with a focus on NTCP and BSEP. Results: This review summarizes the current perception about structure, function, genetic variation, and regulation of NTCP and BSEP, highlights the effects of their defects in some hepatic disorders, and discusses the application prospect of new transcriptional activators in liver diseases. Conclusion: NTCP and BSEP are important proteins for transportation and homeostasis maintenance of bile acids. Further research is needed to develop new models for determining the structure-function relationship of bile acid transporters and screening for substrates and inhibitors, as well as to gain more information about the regulatory genetic mechanisms involved in the processes of liver injury.

Background: Vitamin D has an immunoregulatory action in Inflammatory Bowel Disease (IBD) as well as other immune-mediated disorders. Its influence on intestinal permeability, innate and adaptive immunity, and the composition and diversity of the microbiota contribute to the maintenance of intestinal homeostasis. Patients with IBD have a greater prevalence of vitamin D deficiency than the general population, and a possible association between this deficit and a worse course of the disease. However, intervention studies in patients with IBD have proved inconclusive. Objective: To review all the evidence concerning the role of vitamin D as an important factor in the pathophysiology of IBD, review the associations found between its deficiency and the prognosis of the disease, and draw conclusions for the practical application from the main intervention studies undertaken. Methods: Structured search and review of basic, epidemiological, clinical and intervention studies evaluating the influence of vitamin D in IBD, following the basic principles of scientific data. Results: Vitamin D deficiency is associated with disease activity, quality of life, the consumption of social and healthcare resources, and the durability of anti-TNFα biological treatment. Determination of new metabolites of vitamin D, measurement of its absorption capacity and questionnaires about sun exposure could help identify groups of IBD patients with a special risk of vitamin D deficiency. Conclusion: Well-designed intervention studies are needed in IBD, with probably higher objective plasma doses of vitamin D to establish its efficacy as a therapeutic agent with immunomodulatory properties. Meanwhile, vitamin D deficiency should be screened for and corrected in affected patients in order to achieve adequate bone and phosphocalcic metabolism.

Background: Glucuronidation is one of the most important phase II metabolic pathways. It is catalyzed by a family of UDP-glucuronosyltransferase enzymes (UGTs). UGT1A1 and UGT1A7 catalyze the glucuronidation of a diverse range of medications, environmental chemicals and endogenous compounds. Polymorphisms in the UGT1A gene could potentially be significant for the pharmacological, toxicological and physiological effects of the enzymes. Objective: The UGT1A gene is polymorphic among ethnic groups and the aim of this study was to investigate the different UGT1A1 and UGT1A7 polymorphisms in Circassians, Chechens and Jordanian-Arabs. Methods: A total of 168 healthy Jordanian-Arabs, 56 Circassians and 54 Chechens were included in this study. Genotyping of 20 different Single-nucleotide polymorphism (SNPs) was done by using polymerase chain reaction- DNA sequencing. Results: We found that Circassians and Chechens have significantly higher allele frequencies of UGT1A7*2, UGT1A7*3 and UGT1A7*4 than the Jordanian-Arab population, but all three populations have similar frequencies of UGT1A1*28. Therefore, Circassians and Chechens are expected to have significantly lower levels of the UGT1A7 enzyme with almost 90% of these populations having genes that encode low or intermediate enzyme activity. Conclusion: This inter-ethnic variation in the UGT1A alleles frequencies may affect drug response and susceptibility to cancers among different subethnic groups in Jordan. Our results can also provide useful information for the Jordanian population and for future genotyping of Circassian and Chechen populations in general.

This letter is with reference to a recent article published in Current Drug Metabolism; A System Pharmacology Study for Deciphering Anti Depression Activity of Nardostachys jatamansi. Unfortunately, there is a major error in the “material and method” section of the study, which jeopardizes the study’s goal.