Drug Metabolism Letters - Volume 9, Issue 2, 2015

Licit and illicit drug use is a common complication of pregnancy. Accurate information on drug use is difficult to obtain for many reasons as women fear self-disclosure or consenting for drug testing due to stigma, guilt, and fear of social and legal harm. As information about drug use is clinically very important, biochemical testing is an important adjunct to careful maternal history. In addition, research studies depend on accurate measures of exposure when reporting risks of a substance. This paper delineates available matrices for and methods of biochemical drug testing in pregnant women and neonates.

Nonacoholic fatty liver disease (NAFLD) is a common complication of pediatric obesity in which diet is a major factor in causation and the cornerstone of treatment. In this review, the alterations in hepatic lipid metabolism that contribute to pediatric NAFLD, and impact of dietary proteins, carbohydrates, and fats on hepatic fat metabolism and NAFLD are described. Lastly, dietary recommendations for achieving changes in macronutrient intakes that can be beneficial in the treatment of NAFLD are provided.

This mini-review examines the current state of pediatric physiologically-based pharmacokinetic (PBPK) modeling, including methodologies, approaches, and recent developments. Also discussed are United States regulations that have helped to shape the pediatric PBPK landscape and the ongoing urgent need for pediatric clinical studies. Finally, current pediatric PBPK software as well as the areas of focus for future studies will be reviewed.

Obesity in children is a significant clinical concern. There are many anecdotes and case studies regarding specific reactions of obese children to medications including therapeutic failure, adverse drug reactions and/or requirements for higher weight-adjusted dosing. There isis, however, a lack of basic and clinical data dissecting the mechanisms of these effects on pharmaceutical efficacy and safety. At present it is unknown how much of the difference in drug disposition in obese children can be attributed to obesity, to maturation or to an interaction between the two. Since a major determinant of drug disposition is hepatic metabolism, here we review how obesity alters hepatic drug disposition in children. Basic as well as clinical data summarizing the current knowledge of biochemical, physiological and clinical effects of pediatric obesity on drug disposition are considered. We conclude that there is a dire need for increased research into the direct effects of obesity on absorption, distribution, metabolism and excretion, as well as changes to pharmacokinetic parameters such as bioavailability and clearance. Increased effort in this area may elucidate the effects of obesity on clinical drug disposition with sufficient detail to provide better dosing guidelines where needed for children.

Understanding the detailed ontogeny of xenobiotic metabolizing enzymes is important if we are to be able to predict the risk of toxicity to the developing fetus or the fate of drugs in neonates and children. This review summarizes current knowledge of the development of the major families of conjugating enzymes in humans: the UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, arylamine N-acetyltransferases and methyltransferases; little is known of the last three. Based on the available information, sulfation appears to be the most highly developed pathway during fetal development where glucuronidation in particular is lacking. Following birth, glucuronidation capacity develops rapidly and for many of the enzymes adult capacity occurs in mid-late childhood. The importance of developing pharmacokinetic and physiology-based pharmacokinetic models to support the more informed use of drugs in children is highlighted.

Adverse drug events in children is an under appreciated but significant cause of health care contact resulting in ED visits and hospital admissions with associated resource utilization. In recent years we have started to better understand the impact of ADEs in children but there remains significant questions that must be addressed to further improve our understanding of the etiology of these ADEs and strategies for prevention and management. This paper will describe what is known regarding the frequency, severity, preventability and classification of ADEs in children. It will also describe some of the challenges and unanswered questions regarding patient, drug and system factors, which contribute to ADEs in children. Finally, areas of future research will be identified to further improve our understanding of ADEs in children to inform prevention strategies as well as early recognition and management approaches to minimize the significant ADEs can have on children, families and our health care system.

The functional expression of several hepatic drug metabolizing enzymes and transporters are altered in patients with end-stage renal disease (ESRD). We aimed to assess the effect of ESRD on the expression and function of hepatic reductases. Cytosolic and microsomal fractions were isolated from liver tissue from deceased ESRD (n=10) and deceased control patients (n=11). Gene and protein expression, and metabolic activity of reductases were assessed by conducting qRT-PCR, Western blotting and enzyme kinetics, respectively. A 65% decrease in carbonyl reductase 1 protein expression (p<0.05), and a trend toward decreased reductase mRNA expression and activity was observed in ESRD livers versus controls. These results demonstrate a trend toward decreased functional expression of selective hepatic reductases in ESRD livers, which may partially explain altered pharmacokinetics of CBR1 drug substrates in ESRD. Future studies with larger sample size are warranted to confirm these findings.

DM1, a derivative of maytansine, is the cytotoxic component of the antibody–drug conjugate trastuzumab emtansine (T-DM1). Understanding the disposition and metabolism of DM1 would help to assess (1) any tissue-specific distribution and risk for potential drug–drug interactions and (2) the need for special patient population studies. To this end, the current study determined the disposition and metabolism of DM1 following single intravenous administration of [3H]-DM1 in Sprague Dawley rats. Blood, tissues, urine, bile, and feces were collected up to 5 days after dose administration and analyzed for total radioactivity and metabolites. Results showed that radioactivity cleared rapidly from the blood and quickly distributed to the lungs, liver, kidneys, spleen, heart, gastrointestinal tract, adrenal glands, and other tissues without significant accumulation or persistence. The majority of dosed radioactivity was recovered in feces (~100% of the injected dose over 5 days) with biliary elimination being the predominant route (~46% of the injected dose over 3 days). Excretion in urine was minimal (~5% of the injected dose over 5 days). Mass balance was achieved over 5 days. An analysis of bile samples revealed a small fraction of intact DM1 and a predominance of DM1 metabolites formed through oxidation, hydrolysis, S-methylation, and glutathione and its related conjugates. Collectively, these data demonstrate that DM1 is extensively distributed and quickly cleared from blood, and undergoes extensive metabolism to form multiple metabolites, which are mainly eliminated through the hepatic-biliary route, suggesting that hepatic function (but not renal function) plays an important role in DM1 elimination.

Background: A reliable identification of ADAb represents a fundamental tool in the followup of patients under treatment with anti-TNF drugs. Objectives: To compare three immunoenzymatic assays for anti-adalimumab antibodies (AAA) detection. Methods: The study was performed in 40 patients with chronic inflammatory polyarthritis, comprising both patients showing a good response to adalimumab (ADL) and patients who lost response or did not respond to ADL, recently or in the past (retrospective study). Thus, sera were collected before ADL administration or well after ADL discontinuation. AAA were analysed by three different bridging ELISAs, following manufacturers’ instructions. Results: All methods disclosed negative results in responder patients and univocally recognized 11/31 (35.5%) AAA highpositive samples in non-responder patients, including several cases that had discontinued ADL for a long time (range 3-48 months). Among the overall non-responder patients, 10/31 (32.3%) disclosed concordant clear-cut AAA-negative results, while negative versus low-positive or borderline results were found in another ten non-responder patients, indicating slight differences in sensitivity between the methods, especially in patients who were analysed retrospectively. Methotrexate in combination therapy with ADL tended to be more frequent in AAA-negative, than in AAA-positive patients (52.6% vs. 25%; p=ns). Conclusions: The three bridging ELISA methods under study showed a good agreement and were able to identify uniquely the presence of high positive AAA, even after a long time since ADL discontinuation.