Predicted values for human total clearance of a variety of typical compounds with differently humanized-liver mouse plasma data.
Authors: Nakayama K, Kamimura H, Suemizu H, Yoneda N, Nishiwaki M, Iwamoto K, Mizunaga M, Negoro T, Ito S, Yamazaki H, Nomura Y Abstract Prediction of human pharmacokinetics is important in the preclinical stage. Values for total clearance of compounds from plasma should be one of the most important pharmacokinetic parameters for predictions. Although several physiological and empirical methods including single-species allometry for prediction of values for human clearance of compounds using humanized-liver mice have been reported, further improvement of prediction accuracies would be still expected. To optimize th...
Source: Drug Metabolism and Pharmacokinetics - July 23, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Prediction methods of drug-drug interactions of non-oral CYP3A4 substrates based on clinical interaction data after oral administrations - Validation with midazolam, alfentanil, and verapamil after intravenous administration and prediction for blonanserin transdermal patch.
This study provides DDI prediction methods for non-orally administered CYP3A4 substrates based on clinical DDI data of oral dosages. Gut availability (Fg) and fraction contribution of CYP3A4 to hepatic intrinsic clearance (fmCYP3A4) were predicted by AUC ratio (AUCR) in oral DDI study with/without grapefruit juice, and alteration in intrinsic clearances with/without ketoconazole, respectively. AUCRs of non-orally administered CYP3A4 substrates with/without inhibitors or inducers were predicted with the estimated Fg, fmCYP3A4 and changes in liver CYP3A4 activities with inhibitors/inducers predicted using Simcyp library. DDI...
Source: Drug Metabolism and Pharmacokinetics - July 16, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Novel variants in outer protein surface of flavin-containing monooxygenase 3 found in an Argentinian case with impaired capacity for trimethylamine N-oxygenation.
Authors: Dionisio L, Shimizu M, Stupniki S, Oyama S, Aztiria E, Alda M, Yamazaki H, Spitzmaul G Abstract Flavin-containing monooxygenase 3 (FMO3) is a polymorphic drug metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped a white Argentinian 11-year-old girl by medical sensory evaluation. After pedigree analysis with her brother and parents, this proband showed to harbor a new allele p.(P73L; E158K; E308G) FMO3 in trans configuration with the second new one p.(F140S) FMO3. Recombinant FMO3 proteins of the wild-type and the novel two variants underwent kinetic analyses of their tr...
Source: Drug Metabolism and Pharmacokinetics - July 14, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Pharmacokinetic functions of human induced pluripotent stem cell-derived small intestinal epithelial cells.
Authors: Kabeya T, Mima S, Imakura Y, Miyashita T, Ogura I, Yamada T, Yasujima T, Yuasa H, Iwao T, Matsunaga T Abstract To develop a novel intestinal drug absorption system using intestinal epithelial cells derived from human induced pluripotent stem (iPS) cells, the cells must possess sufficient pharmacokinetic functions. However, the CYP3A4/5 activities of human iPS cell-derived small intestinal epithelial cells prepared using conventional differentiation methods is low. Further, studies of the CYP3A4/5 activities of human iPS-derived and primary small intestinal cells are not available. To fill this gap in our k...
Source: Drug Metabolism and Pharmacokinetics - July 13, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Regional distributions of UDP-glucuronosyltransferase activities toward estradiol and serotonin in the liver and small intestine of cynomolgus macaques.
In this study, UGT activities were analyzed in liver (five lobes) and small intestine (the duodenum and six sections from the proximal jejunum to the distal ileum) using typical probe substrates of human UGTs: 7-hydroxycoumarin, estradiol, serotonin, propofol, and zidovudine. In liver, UGT activities with respect to all substrates were detected, and the activity levels were similar in all liver lobes of the cynomolgus macaques tested. In contrast, in the small intestine, UGT activities toward all substrates were detected, but their levels generally decreased from jejunum to ileum in cynomolgus macaques. The localization of...
Source: Drug Metabolism and Pharmacokinetics - July 13, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Molecular characterization of UDP-glucuronosyltransferases 3A and 8A in cynomolgus macaques.
In this study, cynomolgus macaque UGT3A1, UGT3A2, and UGT8A1 cDNAs were isolated and characterized. Amino acid sequences deduced from cynomolgus UGT3A1, UGT3A2, and UGT8A1 cDNAs were highly identical with their human orthologs (93, 96, and 99%, respectively) and were closely clustered in a phylogenetic tree. In the genome, cynomolgus UGT3A and UGT8A genes were located in the regions corresponding to those of their human orthologs. Among the 10 tissue types analyzed, expression of cynomolgus UGT3A1 and UGT3A2 mRNAs was detected in liver, kidney, and testis; the UGT3A1 and UGT3A2 mRNAs were most abundant in liver and testis,...
Source: Drug Metabolism and Pharmacokinetics - July 11, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

PreMetabo: An in silico phase I and II drug metabolism prediction platform.
This study aimed to develop a drug metabolism prediction platform using knowledge-based prediction models. Site of Metabolism (SOM) prediction models for four cytochrome P450 (CYP) subtypes were developed along with uridine 5'-diphosphoglucuronosyltransferase (UGT) and sulfotransferase (SULT) substrate classification models. The SOM substrate for a certain CYP was determined using the sum of the activation energy required for the reaction at the reaction site of the substrate and the binding energy of the substrate to the CYP enzyme. Activation energy was calculated using the EaMEAD model and binding energy was calculated ...
Source: Drug Metabolism and Pharmacokinetics - July 4, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Inhibitory effects of sesamin on CYP2C9-dependent 7-hydroxylation of S-warfarin.
In this study, we found that sesamin competitively inhibited the 7-hydroxylation activity of S-warfarin in human liver microsomes with a Ki value of 15.7 μM. In addition, the recombinant CYP2C9-dependent 7-hydroxylation activity of S-warfarin was competitively inhibited by sesamin with a Ki value of 13.1 μM. These results are consistent with the fact that sesamin is a good substrate of CYP2C9, and its activity follows Michaelis-Menten kinetics. As the plasma concentration of sesamin after its administration is usually lower than 0.01 μM, the inhibition of S-warfarin metabolism by sesamin does not ap...
Source: Drug Metabolism and Pharmacokinetics - July 1, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Increased plasma concentrations of an antidyslipidemic drug pemafibrate co-administered with rifampicin or cyclosporine A in cynomolgus monkeys genotyped for the organic anion transporting polypeptide 1B1.
Authors: Ogawa SI, Shimizu M, Kamiya Y, Uehara S, Suemizu H, Yamazaki H Abstract In vitro permeability and in vivo pharmacokinetics of pemafibrate were investigated in human intestinal and animal models untreated or pretreated with cyclosporine A or rifampicin to evaluate any drug interactions. Ratios of basal to apical apparent permeability (Papp) over apical to basal Papp in the presence of pH gradients decreased from 0.37 to 0.080 on rifampicin co-incubation, suggesting active transport of pemafibrate from basal to apical sides in intestinal models. Plasma concentrations of intravenously administered p...
Source: Drug Metabolism and Pharmacokinetics - July 1, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Pharmacokinetics of omeprazole in rats with dextran sulfate sodium-induced ulcerative colitis.
This study investigated the pharmacokinetics of omeprazole in rats with UC induced by dextran sulfate sodium (DSS). The pharmacokinetics of intravenously administered omeprazole (20 mg/kg) was investigated in normal and UC rats using LC-MS/MS. The formation of 5-OH omeprazole, a main metabolite of omeprazole, in rat liver microsomes (RLMs) from normal and UC rats was compared. The protein levels of CYP1A2, CYP2D1, and CYP3A1 in the liver were measured by Western blot. Compared with normal rats, UC rats had increased plasma concentrations of omeprazole, resulting in an increased AUC0-240 min and decreased CL. DSS ...
Source: Drug Metabolism and Pharmacokinetics - May 2, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Species differences in liver accumulation and metabolism of nucleotide prodrug sofosbuvir.
Authors: Wang T, Babusis D, Park Y, Niu C, Kim C, Zhao X, Lu B, Ma B, Muench RC, Sperger D, Ray AS, Murakami E Abstract Sofosbuvir (SOF) is a nucleotide prodrug which has been used as a backbone for the clinical treatment of hepatitis C viral infection. Because sofosbuvir undergoes complex first pass metabolism, including metabolic activation to form its pharmacologically active triphosphate (GS-331007-TP) to inhibit the viral RNA polymerase in the liver, it is difficult to project the human dose for clinical evaluation based on preclinical data. Selecting an appropriate animal model for drug exposure in the target...
Source: Drug Metabolism and Pharmacokinetics - May 1, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Versatile applicability of a grid-based CYP3A4 Template to understand the interacting mechanisms with the small-size ligands; part 3 of CYP3A4 Template study.
Authors: Yamazoe Y, Goto T, Tohkin M Abstract Modes of interactions of small ligands with CYP3A4 have been defined using the Template established in our previous studies (DMPK. 34: 113-125 2019 and 34 351-364 2019). Interactions of polyaromatic hydrocarbons such as benzo[a]pyrene, pyrene and dibenzo[a,j]acridine were refined with the idea of Right-side movement of ligands at Rings A and B of Template. Expected formation of metabolites from the placements faithfully matched with experimentally observed sites of their metabolisms and also with preferred orders of regio-isomeric metabolite abundances in recombina...
Source: Drug Metabolism and Pharmacokinetics - April 27, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor.
In conclusion, low-dose dotinurad exhibited excellent pharmacological effects as well as ideal PK properties as a SURI. PMID: 32327267 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - April 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Whole-cell dependent biosynthesis of N- and S-oxides using human flavin containing monooxygenases expressing budding yeast.
In this study, we developed a heterologous expression system for human FMOs, including FMO1-FMO5, in Saccharomyces cerevisiae and examined its N- and S-oxide productivity. The recombinant yeast cells expressed each of the FMO successfully, and the FMO4 transformant produced N- and S-oxide metabolites at several milligrams per liter within 24 h. This whole-cell dependent biosynthesis enabled the production of N- and S-oxides without the use of the expensive cofactor NADPH. Such novel yeast expression system could be a powerful tool for the production of oxide metabolites. PMID: 32305264 [PubMed - as supplied by pub...
Source: Drug Metabolism and Pharmacokinetics - April 21, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Extrapolation for a pharmacokinetic model for acetaminophen from adults to neonates: A Latin Hypercube Sampling analysis.
Authors: Zhang S, Zhang E, Ho H Abstract Physiological and drug-specific parameters need to be adjusted when extrapolating a pharmacokinetic (PK) model from adults to neonates, so as to reproduce the time profiles of the studied drug(s) consistent with clinical, in vivo data or in vitro cell line measurements. In this paper we present a parameter analysis method, i.e. the Latin Hypercube Sampling (LHS) method for an acetaminophen (APAP) PK model. The original model consists of two compartments (the blood and the urine) with Michaelis-Menten kinetic parameters determined for APAP and its metabolites. The p...
Source: Drug Metabolism and Pharmacokinetics - April 21, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Comparison of the inducibility of CYP mRNA exposed to typical inducers in fresh and cryopreserved cynomolgus monkey hepatocytes.
Authors: Koeda A, Iwao T, Nakanishi A, Mizuno S, Yamashita M, Sakai Y, Nakamura K, Matsunaga T Abstract Herein, we evaluated CYPs and their nuclear receptor mRNA induction by exposure to typical inducers, omeprazole, rifampicin, and phenobarbital in cynomolgus monkey hepatocytes. Six freshly-isolated hepatocytes and 6 cryopreserved hepatocytes from cynomolgus monkey liver were prepared for a 14-day monolayer culture, 28-day co-culture with feeder cells, and 28-day 3D spheroid culture with feeder cells. Omeprazole and rifampicin respectively induced CYP1A1 and CYP3A8 mRNAs, while phenobarbital induced CYP2C43, CYP2C...
Source: Drug Metabolism and Pharmacokinetics - April 20, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Establishment of MDR1-knockout human induced pluripotent stem cell line.
Authors: Negoro R, Kawai K, Ichikawa M, Deguchi S, Takayama K, Mizuguchi H Abstract Multiple drug resistance 1 (MDR1) is highly expressed in various organs, including the liver, small intestine, and blood-brain barrier (BBB). Because MDR1 plays important roles in the excretion of many drugs, it is necessary to evaluate whether drug candidates are potential substrates of MDR1. Recently, many researchers have shown that human induced pluripotent stem (iPS) cell-derived differentiated cells such as hepatocytes and enterocytes can be applied for pharmacokinetic testing. Here, we attempted to generate MDR1-knockout (KO)...
Source: Drug Metabolism and Pharmacokinetics - April 20, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Cellular uptake properties of lamotrigine in human placental cell lines: Investigation of involvement of organic cation transporters (SLC22A1-5).
Authors: Hasegawa N, Furugen A, Ono K, Koishikawa M, Miyazawa Y, Nishimura A, Umazume T, Narumi K, Kobayashi M, Iseki K Abstract Lamotrigine (LTG) is an important antiepileptic drug for the treatment of seizures in pregnant women with epilepsy. However, it is not known if the transport of LTG into placental cells occurs via a carrier-mediated pathway. The aim of this study was to investigate the uptake properties of LTG into placental cell lines (BeWo and JEG-3), and to determine the involvement of organic cation transporters (OCTs, SLC22A1-3) and organic cation/carnitine transporter (OCTNs, SLC22A4-5) in the uptak...
Source: Drug Metabolism and Pharmacokinetics - April 20, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

13C-caffeine breath test identifies single nucleotide polymorphisms associated with caffeine metabolism.
Authors: Ishii M, Ishii Y, Nakayama T, Takahashi Y, Asai S Abstract We performed a caffeine (N-3-methyl-13C) breath test (CafeBT) to determine whether it can be employed to identify caffeine metabolism-associated single nucleotide polymorphisms. The study included 130 healthy adults (mean age: 21.9 years). Saliva was collected using an Oragene®•DNA saliva collection kit. Breath samples were collected from the subjects. The subjects orally ingested 100 mg 13C-caffeine dissolved in distilled water. Subsequently, breath samples were collected in bags every 10 min for a total of 90 min. An analy...
Source: Drug Metabolism and Pharmacokinetics - April 20, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Functional characterization of monocarboxylate transporter 12 (SLC16A12/MCT12) as a facilitative creatine transporter.
This study was performed to determine the functional and molecular characteristics of MCT12 in mammalian cells. The results showed that the uptake of [14C]creatine was not significantly increased in HEK293 cells transiently expressing MCT12 with or without CD147, a molecular chaperone, compared with mock cells. When [14C]creatine was accumulated in the cells with the aid of SLC6A8/CRT1, a concentrative creatine transporter, followed by assessing the remaining intracellular [14C]creatine after initiating efflux, coexpression of MCT12 resulted in a decrease in the intracellular [14C]creatine and remarkably enhanced the ...
Source: Drug Metabolism and Pharmacokinetics - April 8, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Interleukin-1 β and tumor necrosis factor-α affect cytochrome P450 expression in cynomolgus macaque hepatocytes.
In this study, the effects of cytokines on P450 expression were investigated using the quantitative polymerase chain reaction to evaluate mRNA expression. Hepatocytes from cynomolgus macaques were treated with lipopolysaccharide and various cytokines, including interleukin (IL)-1β, IL-2, IL-6, interferon-γ, and tumor necrosis factor-α, and the expression levels of 11 P450s were compared with those of solvent-treated controls. Tumor necrosis factor-α significantly decreased cynomolgus P450 2C8 and 2C76 mRNA expression in multiple lots of cynomolgus hepatocytes investigated. IL-1β significantly de...
Source: Drug Metabolism and Pharmacokinetics - April 8, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Simple pharmacokinetic models accounting for drug monitoring results of atomoxetine and its 4-hydroxylated metabolites in Japanese pediatric patients genotyped for cytochrome P450 2D6.
Authors: Notsu Y, Shimizu M, Sasaki T, Nakano A, Ota M, Yoshida S, Yamazaki H Abstract Atomoxetine is an approved medicine for attention-deficit/hyperactivity disorder and a cytochrome P450 2D6 (CYP2D6) probe substrate. Simple physiologically based pharmacokinetic (PBPK) models and compartment models were set up to account for drug monitoring results of 33 Japanese patients (6-15 years of age) to help establish the correct dosage for the evaluation of clinical outcomes. The steady-state one-point drug monitoring data for the most participants indicated the extensive biotransformation of atomoxetine to 4-hydroxyatom...
Source: Drug Metabolism and Pharmacokinetics - March 19, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Synthesis and evaluation of nevirapine analogs to study the metabolic activation of nevirapine.
In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than...
Source: Drug Metabolism and Pharmacokinetics - March 19, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Preface.
Authors: Takada T, Nishimura T PMID: 32089247 [PubMed - in process] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - February 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Association between bisoprolol plasma concentration and worsening of heart failure: (CVI ARO 6).
CONCLUSIONS: Bis-PC was increased by age and renal dysfunction, and high Bis-PC was associated with worsening of HF in elderly and HFpEF patients. Care should be taken to avoid overdose. PMID: 32044255 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - February 13, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Suppression of P-glycoprotein by cigarette smoke extract in human lung-derived A549/P-gp cells.
Authors: Takano M, Higa S, Furuichi Y, Naka R, Yumoto R Abstract Effect of long-term treatment with cigarette smoke extract (CSE) on the function and expression of P-glycoprotein (P-gp) in lung alveolar epithelial cells was examined using A549/P-gp cell line expressing P-gp. CSE treatment suppressed P-gp activity in a concentration- and treatment time-dependent manner. The suppression of P-gp activity by CSE was irreversible for at least 96 h after removal of CSE. In addition, CSE treatment suppressed the expression of P-gp mRNA and protein. In order to understand the mechanisms underlying P-gp suppression by ...
Source: Drug Metabolism and Pharmacokinetics - February 11, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Establishment of a primary human hepatocyte spheroid system for evaluating metabolic toxicity using dacarbazine under conditions of CYP1A2 induction.
Authors: Mizoi K, Hosono M, Kojima H, Ogihara T Abstract Some drugs induce cytochrome P450s (CYPs), and thus may cause increased metabolic toxicity from concomitantly administered agents. Hence, we need a means of evaluating the potential of compounds to cause drug-induced liver injury (DILI) under conditions where inducers of CYP1A2 are present. Here, we present a system for evaluating CYP1A2-mediated metabolic toxicity using three-dimensional (3D) cultures of primary human hepatocyte spheroids treated with the CYP1A2 inducer omeprazole (OPZ). As a test substrate, we employed dacarbazine (DTIC), which causes toxic...
Source: Drug Metabolism and Pharmacokinetics - February 11, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

CYP2D6 genotyping analysis and functional characterization of novel allelic variants in a Ni-Vanuatu and Kenyan population by assessing dextromethorphan O-demethylation activity.
Authors: Gutiérrez Rico EM, Kikuchi A, Saito T, Kumondai M, Hishinuma E, Kaneko A, Chan CW, Gitaka J, Nakayoshi T, Oda A, Saito S, Hirasawa N, Hiratsuka M Abstract While CYP2D6 allele and phenotype frequencies have been extensively studied, currently, very little ethnically specific data is available regarding the East African and South Pacific region, including Kenya and Vanuatu. The absence of information regarding gene polymorphisms and their resulting clinical effects in these populations may hinder treatment strategies and patient outcome. Given the scarceness of CYP2D6 related data in these populations...
Source: Drug Metabolism and Pharmacokinetics - February 11, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Factor Xa inhibitors in clinical practice: Comparison of pharmacokinetic profiles.
Authors: Goto E, Horinaka S, Ishimitsu T, Kato T Abstract BACKGROUND: The anticoagulant actions of oral direct factor Xa (FXa) inhibitors can be inferred from their observed plasma concentrations; however, the steady-state pharmacokinetics (PK) of different FXa inhibitors have not been compared in clinically. METHODS: The sensitivity of the rivaroxaban, apixaban, and edoxaban in the STA-Liquid Anti-FXa assay were compared, and the anti-FXa plasma concentrations were measured for PK assessments. Nonlinear mixed-effects modeling was used to assess population PK in 329 patients with nonvalvular atrial fibrillation...
Source: Drug Metabolism and Pharmacokinetics - February 4, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Clinical study designs and patient selection methods based on genomic biomarkers: Points-to-consider documents.
Authors: Tohkin M, Saito Y, Yagi S, Asano K, Maekawa K, Osabe M, Iida S, Miyata N Abstract Recently, genomic biomarkers have been widely used clinically for prediction of the efficacy and safety of pharmacotherapy and diagnosis and prognosis of pathological conditions. Therefore, genomic biomarkers are anticipated to accelerate not only precision medicine for pharmacotherapy but also development of molecularly targeted drugs. Because the design of clinical studies involving biomarkers may differ from conventional clinical study designs, a concept paper focused on clinical studies and patient selection methods based...
Source: Drug Metabolism and Pharmacokinetics - February 4, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

A summary of the current drug interaction guidance from the European Medicines Agency and considerations of future updates.
Authors: Cole S, Kerwash E, Andersson A Abstract The current EMA drug interaction guideline was published in 2012. This guideline gives important recommendations on the information required to elucidate the interaction potential of an investigational drug, both as effects of the investigational drug on the PK of other drugs and effects of other medicinal products on the PK of the investigational drug. Additional information on the use of PBPK modelling to inform drug interaction information, is also available in the guideline on the reporting of physiologically based modelling and simulation (2018). Some points of ...
Source: Drug Metabolism and Pharmacokinetics - February 1, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Quantitative application of flow cytometry for the analysis of circulating human T cells: A preclinical pharmacokinetic study.
Authors: Yamamoto S, Matsumoto SI, Shimizu H, Hirabayashi H Abstract As the application of flow cytometry to a quantitative pharmacokinetic study with adoptive T cell therapy is new, we aimed to investigate the quantitativity of flow cytometry-based analysis for the pharmacokinetic assessment of circulating human T cells in a preclinical study. We evaluated the selectivity, linearity, accuracy, precision, and sensitivity of flow cytometry-based analysis for human CD8+ T cells in immunodeficient mouse blood. The CD3/8/45-positive cell population was successfully distinguished from the negative population. Linear reg...
Source: Drug Metabolism and Pharmacokinetics - January 26, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Cloning and tissue expression of cytochrome P450 2S1, 4V2, 7A1, 7B1, 8B1, 24A1, 26A1, 26C1, 27A1, 39A1, and 51A1 in marmosets.
In this study, marmoset cytochrome P450 (P450) 2S1, 4V2, 7A1, 7B1, 8B1, 24A1, 26A1, 26C1, 27A1, 39A1, and 51A1 cDNAs were isolated from marmoset tissues (brains, lungs, livers, kidneys, and jejunums). Deduced amino acid sequences (89-98% homologous) of the marmoset P450 gene suggested similarity of molecular characteristics of marmoset P450s to human counterparts, compared with those of pig, rabbit, and rodents. Phylogenetic analysis using amino acid sequences indicated 11 marmoset P450 forms clustered with those of human and other primate counterparts, suggesting marmoset P450s have an evolutionary close relationship to h...
Source: Drug Metabolism and Pharmacokinetics - January 26, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Pharmacokinetic modeling and simulation for dose rationale of doripenem in neonates and infants.
Authors: Matsuo Y, Matsumoto S, Wajima T, Matsubara K Abstract The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients MIC against MIC of 2 μg/mL in all age groups. These results would be useful for understanding the PKPD characteristics of doripenem, which could provide essential information on optimal therapeutic treatment for neonates and infants. PMID: 31969257 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - January 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Prediction of regioselectivity and preferred order of CYP1A1-mediated metabolism: Solving the interaction of human and rat CYP1A1 forms with ligands on the template system.
Authors: Yamazoe Y, Yoshinari K Abstract A simulation system for ligand interaction of human CYP1A1 has been developed using "Template" composed of hexagonal grids, as a modification of CYP1A2 system established previously. Differing from CYP1A2 Template, Site of Oxidation of CYP1A1 was located one-grid (Ring) away horizontally from Trigger-Region (Ring B) on CYP1A1 Template. Simultaneous interaction at Site of Oxidation and Trigger-Region as uni- or bi-molecule binding was maintained with CYP1A1 as well as CYP1A2 for the functional contributions. Reciprocal comparison of simulation results with experimen...
Source: Drug Metabolism and Pharmacokinetics - January 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

rs622342A > C in SLC22A1 is associated with metformin pharmacokinetics and glycemic response.
rs622342A>C in SLC22A1 is associated with metformin pharmacokinetics and glycemic response. Drug Metab Pharmacokinet. 2019 Nov 01;: Authors: Naja K, El Shamieh S, Fakhoury R Abstract Polymorphisms in SLC22A1 lead to variability in metformin clinical efficacy. Sixty-three Lebanese patients with type 2 diabetes who administered metformin, were followed up for six months and genotyped for rs622342A>C. The area under the plasma concentration-time curve and the maximum concentration of metformin was highest in CC patients (P ≤ 0.03). There was a significant difference between groups in th...
Source: Drug Metabolism and Pharmacokinetics - January 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2.
Authors: Morita T, Akiyoshi T, Sato R, Katayama K, Yajima K, Kataoka H, Imaoka A, Sugimoto Y, Ohtani H Abstract Organic anion-transporting polypeptide (OATP) 1A2 is expressed on the apical sides of intestinal and renal epithelial cells and considered to be involved in the intestinal absorption and renal reabsorption of drugs. Although the transport activity of OATP1A2 is considered to be pH-dependent, the effects of pH on its kinetic parameters and on the potency of OATP1A2 inhibitors are yet to be elucidated. Some OATP are known to have multiple binding sites (MBS), but it remains unclear whether OATP1A2 has MBS. ...
Source: Drug Metabolism and Pharmacokinetics - January 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Developmental changes in transporter and receptor protein expression levels at the rat blood-brain barrier based on quantitative targeted absolute proteomics.
Authors: Omori K, Tachikawa M, Hirose S, Taii A, Akanuma SI, Hosoya KI, Terasaki T Abstract The blood-brain barrier (BBB) transport systems regulate the supply of nutrients, amino acids, vitamins, and hormones to the developing brain, as well as blocking the entry of xenobiotics and drugs. The purpose of this study was to clarify the developmental changes in the absolute protein expression levels of BBB transport-related proteins in developing rat brain capillaries, using quantitative targeted absolute proteomics (QTAP). The changing patterns of ATP-binding cassette (ABC) and solute carrier (SLC) transporters, rece...
Source: Drug Metabolism and Pharmacokinetics - January 25, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Numerical analysis of apparent decitabine uptake in HCT116 cells: Incorporation of a bidirectional first-order kinetic parameter for ENT1 transport and Michaelis-Menten parameters for subsequent phosphorylation.
In conclusion, DAC uptake mainly via ENT1 may be described by a bidirectional first-order kinetic parameter, while phosphorylation by dCK may be described by Michaelis-Menten parameters. PMID: 31964620 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - January 24, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

mRNA levels of drug-metabolizing enzymes in 11 brain regions of cynomolgus macaques.
In this study, by using the quantitative polymerase chain reaction, we measured the mRNA levels of 38 cynomolgus drug-metabolizing enzymes, including 19 P450s, 10 UDP-glycosyltransferases, and 9 other enzymes, in 11 brain regions. Among these drug-metabolizing enzymes, expression of 32 enzyme mRNAs were detected in one or more brain regions, indicating their possible roles in the brain. Further investigation of metabolic activities would facilitate better understanding of the importance of these enzymes in the brain. PMID: 31964621 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - January 24, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Cisplatin, rather than oxaliplatin, increases paracellular permeability of LLC-PK1 cells via activating protein kinase C.
In conclusion, pharmacodynamic mechanisms via PKC could explain the difference in nephrotoxicity between cisplatin and oxaliplatin. PMID: 31964622 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - January 24, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Recent progress in in  vivo phenotyping technologies for better prediction of transporter-mediated drug-drug interactions.
Recent progress in in vivo phenotyping technologies for better prediction of transporter-mediated drug-drug interactions. Drug Metab Pharmacokinet. 2020 Jan 03;: Authors: Maeda K Abstract Clinical reports on transporter-mediated drug-drug interactions (TP-DDIs) have rapidly accumulated and regulatory guidance/guidelines recommend that sponsors consider performing quantitative prediction of TP-DDI risks in the process of drug development. In vitro experiments for characterizing the function of drug transporters have been established and various parameters such as the inhibition constant (Ki) o...
Source: Drug Metabolism and Pharmacokinetics - January 19, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Identification and quantitation of enzyme and transporter contributions to hepatic clearance for the assessment of potential drug-drug interactions.
Authors: Kimoto E, Obach RS, Varma MVS Abstract Drug-drug interactions (DDIs) involving drug-metabolizing enzymes and membrane transporters can lead to alteration in substrate drug (victim) exposure, and can influence the pharmacological and toxicological effects. In order to predict DDI potential, it is important to quantitatively characterize the major enzyme(s) and/or transporter(s) involved in the clearance of drugs, in terms of fraction metabolized (fm) and fraction transported (ft). In this review, we discuss a strategy using Extended Clearance Classification System (ECCS) to identify the clearance mechanism(...
Source: Drug Metabolism and Pharmacokinetics - January 19, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Identification of non-P450 enzymes involved in the metabolism of new drugs: Their significance in drug interaction evaluation and prodrug disposition.
Authors: Nishiya Y, Suzuki E, Ishizuka T, Kazui M, Sakurai H, Nakai D PMID: 31926835 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - January 15, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Recent advances in preclinical in  vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters.
This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro-in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approac...
Source: Drug Metabolism and Pharmacokinetics - January 8, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Computational prediction of cytochrome P450 inhibition and induction.
Authors: Kato H Abstract Cytochrome P450 (CYP) enzymes play an important role in the phase I metabolism of many xenobiotics. Most drug-drug interactions (DDIs) associated with CYP are caused by either CYP inhibition or induction. The early detection of potential DDIs is highly desirable in the pharmaceutical industry because DDIs can cause serious adverse events, which can lead to poor patient health and drug development failures. Recently, many computational studies predicting CYP inhibition and induction have been reported. The current computational modeling approaches for CYP metabolism are classified as ligand-...
Source: Drug Metabolism and Pharmacokinetics - January 8, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information.
This article aims to present an overview of development process of the new Japanese guideline for investigating drug interactions and show the impact of implementating this guideline on drug interaction evaluations, thereby providing future perspectives of regulatory activities on drug interactions. PMID: 31902469 [PubMed - as supplied by publisher] (Source: Drug Metabolism and Pharmacokinetics)
Source: Drug Metabolism and Pharmacokinetics - January 8, 2020 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Evaluation of drug-drug interactions in drug metabolism: Differences and harmonization in guidance/guidelines.
Authors: Iwatsubo T Abstract The U.S. Drugs and Food Administration (FDA) and the Ministry of Health, Labor and Welfare of Japan (MHLW) issued the drastically revised draft guidance and final guideline on drug-drug interactions (DDI) in 2017 and 2018, respectively. One of the most drastic changes for the evaluation of inhibition potential of drug metabolizing enzymes in the liver using a basic model in these guidance and guideline are represented by the concept to use the unbound maximum concentration in the systemic circulation as the investigational drug concentration instead of the total maximum concentration an...
Source: Drug Metabolism and Pharmacokinetics - November 25, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

Influence of gastrointestinal activity on the absorption of nilotinib.
Authors: Sasaki M, Aoyama T, Sugawara M, Takekuma Y Abstract Nilotinib has bioavailability (BA) of only about 25% or less. The purpose of this study was to evaluate the influence of gastrointestinal activity on the absorption of nilotinib. In order to change gastrointestinal activity, mosapride was used for enhancement and butylscopolamine was used for suppression. Experiments on oral administration of nilotinib using rats whose gastrointestinal activity was altered by mosapride or butylscopolamine were carried out. The results of oral administration of acetaminophen to rats with peristalsis movement changed showed...
Source: Drug Metabolism and Pharmacokinetics - November 19, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf ®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients.
The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients. Drug Metab Pharmacokinet. 2019 Oct 21;: Authors: Sukkha S, Chindavijak B, Nosoongnoen W, Phakdeekitchareon B, Kitiyakara C, Sumethkul V Abstract Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT reci...
Source: Drug Metabolism and Pharmacokinetics - November 16, 2019 Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research