Discover the most talked about and latest scientific content & concepts.

Journal: Drug metabolism and pharmacokinetics


 A pharmacokinetic/pharmacodynamic (PK/PD) analysis is important in antibiotic chemotherapy. Basically, the in vivo efficacy of antibiotics that exert concentration-dependent effects can be predicted using conventional PK/PD indices such as the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC) and/or the ratio of the maximum plasma concentration to MIC (Cmax/MIC), whereas that of antibiotics with time-dependent effects can be determined using the period of time for which the drug concentration exceeds the MIC (time above MIC [TAM]). However, an optimal PK/PD index remains to be established for some antibiotics. Thus, a PK/PD model, which describes the PK profile and effect of an antibiotic, was developed, and the results obtained from this model were interpreted to form a PK/PD index map to assess the optimal PK/PD index for the antibiotic. The findings from the map were generally consistent with clinical outcomes even for the antibiotics which became the exception by the conventional classification. For example, AUC/MIC was an optimal index for azithromycin despite its time-dependent bactericidal activity, and Cmax/MIC was a poor index for arbekacin despite its concentration-dependent profile. Thus, the map would be useful for selecting the appropriate PK/PD index for an antibiotic.

Concepts: Time, Effectiveness, Ratio, Antibiotic, Unified Modeling Language, Erythromycin, Bactericide, Ruby


This study aimed to evaluate the potential of α-cedrene as a new anti-obesity drug by characterizing absorption, metabolism and pharmacokinetics in rats. α-Cedrene was administered intravenously (10 and 20 mg/kg) and orally (50 and 100 mg/kg) to female and male Sprague-Dawley rats. Blood, tissues, urine, and feces were collected at predetermined times. α-Cedrene concentrations were determined by a validated gas chromatography-tandem mass spectrometry (GC-MS/MS). A gas chromatography-mass selective detection (GC-MSD) method was used to identify the major metabolite. After i.v. injection, α-cedrene exhibited a rapid clearance (98.4-120.3 ml/min/kg), a large distribution volume (35.9-56.5 l/kg), and a relatively long half-life (4.0-6.4 h). Upon oral administration, it was slowly absorbed (Tmax = 4.4 h) with bioavailability of 48.7-84.8%. No gender differences were found in its pharmacokinetics. Upon oral administration, α-cedrene was highly distributed to tissues, with the tissue-to-plasma partition coefficients (Kp) far greater than unity for all tissues. In particular, its distribution to lipid was notably high (Kp = 132.0) compared to other tissues. A mono-hydroxylated metabolite was identified as a preliminary metabolite in rat plasma. These results suggest that α-cedrene has the favorable pharmacokinetic characteristics to be further tested as an anti-obesity drug in clinical studies.

Concepts: Pharmacology, Male, Metabolism, Gender, Distribution, Absorption, Pharmacokinetics, Bioavailability


Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Although the in vivo and in vitro effects of fisetin and its metabolites are frequently reported, studies on herb-drug interactions have not yet been performed. This study was designed to investigate the inhibitory effect of fisetin and geraldol on eight isoforms of human cytochrome P450 (CYP) by using cocktail assay and LC-MS/MS analysis. The selective inhibition of CYP2C8-catalyzed paclitaxel hydroxylation by fisetin and geraldol were confirmed in pooled human liver microsomes (HLMs). In addition, an IC50shift assay under different pre-incubation conditions confirmed that fisetin and geraldol shows a reversible concentration-dependent, but not mechanism-based, inhibition of CYP2C8. Moreover, Michaelis-Menten, Lineweaver-burk plots, Dixon and Eadie-Hofstee showed a non-competitive inhibition mode with an equilibrium dissociation constant of 4.1 μM for fisetin and 11.5 μM for geraldol, determined from secondary plot of the Lineweaver-Burk plot. In conclusion, our results indicate that fisetin showed selective reversible and non-competitive inhibition of CYP2C8 more than its main metabolite, geraldol, in HLMs.

Concepts: Enzyme kinetics, Metabolism, Cytochrome P450, Paracetamol, CYP2C9, Lineweaver–Burk plot, Michaelis–Menten kinetics, CYP2C8


ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [14C]ASP7991 were investigated in six healthy male subjects after a single oral dose of [14C]ASP7991 [1 mg, 18.5 kBq (500 nCi)] in solution. [14C] radioactivity in plasma, urine and feces was analyzed using Accelerator mass spectrometry. ASP7991 was rapidly absorbed, metabolized and excreted. Mean recovery of [14C] radioactivity in urine and feces was 30.08% and 49.31%, respectively, and mean total recovery of [14C] radioactivity was 79.39%. The majority of [14C] radioactivity in urine and feces was excreted within the first 72 h following administration. Seven metabolites were detected in plasma, urine and feces samples, and their structures were determined by mass spectrometry. The main metabolic pathways of ASP7991 in humans were predicted to be N-dealkylation, followed by N-acetylation and taurine conjugation to a carboxylic acid moiety. Our findings show that a mass balance study using micro radioactivity doses is suitable for elucidating the pharmacokinetics of the absorption, metabolism and excretion of administered drugs.

Concepts: Protein, Amino acid, Metabolism, Mass spectrometry, Parathyroid hormone, Parathyroid gland, Hypoparathyroidism, Hyperparathyroidism


This study was undertaken to evaluate the performance of anti-drug antibody (ADA) assays constructed by each participating company using common samples including ADA, drug and human serum. The ADA assays constructed by each company showed good sensitivity and precision for evaluation of ADA. Cut points for screening and confirmatory assays and assay selectivity were determined by various calculation methods. In evaluations of blind ADA samples, nearly similar results were obtained by the study companies in determinations of whether samples were positive or negative except at the lowest sample concentration (5 ng/mL). In measurement of drug tolerance, for almost samples containing ADA and drugs, more positive results were obtained in assays using acid dissociation compared to those without acid dissociation. Overall, the performance of ADA assays constructed by the 10 companies participating in this study was acceptable in terms of sensitivity and reproducibility for detection and evaluation of immunogenicity in both patients and healthy subjects. On the other hand, based on results for samples containing ADA and drugs, validity of results for ADA assays conducted without acid dissociation was less meaningful and more difficult to evaluate. Thus, acid dissociation was confirmed to be useful for improving drug tolerance.

Concepts: Type I and type II errors, Sensitivity and specificity, Drug, ELISA, ELISPOT, Drug addiction, Selectivity, Illegal drug trade


Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method. Furthermore, high-resolution multiple reaction monitoring (MRM-HR), a targeted proteomic approach, was utilized to compare the expressions of pre-selected DMEs between human livers and the cell lines. In general, the SWATH quantifications were in good agreement with the MRM-HR analysis. Over 3000 protein groups were quantified in the cells and human livers, and the proteome profiles of human livers significantly differed from the cell lines. Among the 101 DMEs quantified with MRM-HR, most were expressed at substantially lower levels in the cell lines. Thus, appropriate caution must be exercised when using these cell lines for the study of hepatic drug metabolism and toxicity.

Concepts: Protein, Cell, Metabolism, Enzyme, Glucose, Liver, Proteomics, Drug metabolism


More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans.

Concepts: Pharmacology, Alcohol, Metabolism, Enzyme, Drug, Drugs, Carboxylic acid, Adverse drug reaction


Although animal experiments are indispensable for preclinical screening in the drug discovery process, various issues such as ethical considerations and species differences remain. To solve these issues, cell-based assays using human-derived cells have been actively pursued. However, it remains difficult to accurately predict drug efficacy, toxicity, and organs interactions, because cultivated cells often do not retain their original organ functions and morphologies in conventional in vitro cell culture systems. In the μTAS research field, which is a part of biochemical engineering, the technologies of organ-on-a-chip, based on microfluidic devices built using microfabrication, have been widely studied recently as a novel in vitro organ model. Since it is possible to physically and chemically mimic the in vitro environment by using microfluidic device technology, maintenance of cellular function and morphology, and replication of organ interactions can be realized using organ-on-a-chip devices. So far, functions of various organs and tissues, such as the lung, liver, kidney, and gut have been reproduced as in vitro models. Furthermore, a body-on-a-chip, integrating multi organ functions on a microfluidic device, has also been proposed for prediction of organ interactions. We herein provide a background of microfluidic systems, organ-on-a-chip, Body-on-a-chip technologies, and their challenges in the future.

Concepts: Cell, Biology, Organelle, Biotechnology, Future, Chemistry, Organ, Microfluidics


Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery.

Concepts: Scientific method, Metabolism, Prediction, Futurology, Liver, Glycogen, Drug metabolism, Hepatocyte


Microphysiological systems (MPS) are currently attracting a lot of interest from pharmaceutical companies worldwide. In the United States and European Union, several large government projects related to MPS have been initiated, and, in Japan, pharmaceutical companies interested in MPS are watching the recent trends and developments in the field. In July 2017, the Japan Agency for Medical Research and Development initiated a research program to develop chip-based MPS. In this review, we examine the technical aspects of commercializing chip-based MPS.

Concepts: European Union, United States, United Kingdom, Japan, Research and development