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"Physiologically-based pharmacokinetic (PBPK) modeling is becoming increasingly important in human health risk assessments and in supporting pharmacodynamic modeling for toxic responses. Organized by classes of compounds and modeling purposes so users can quickly access information, this is the first comprehensive reference of its kind.This book presents an overview of the underlying principles of PBPK model development. Then it provides a compendium of PBPK modeling information, including historical development, specific modeling challenges, and current practices for, halogenated alkanes, alkene and aromatic compounds, reactive vapors in the nasal cavity, alkanes, oxyhydrocarbons, and related compounds, pesticides and persistent organic pollutants, dioxin and related compounds, metals and inorganic compounds, drugs, antineoplastic agents, perinatal transfer, mixtures, dermal exposure models."

"Peningkatan DNA adduct yaitu 8-OHdG dipengaruhi oleh adanya xenobiotik yang bersifat toksik dan karsinogenik. Xenobiotik yang digunakan pada penelitian ini adalah paraquat diklorida sebagaimana diketahui paraquat diklorida merupakan pestisida golongan II berdasarkan WHO yang memikili efek berbahaya karena dapat menyebabkan mutasi gen sehingga berdampak karsinogenik. Penambahan ion logam Cu(II) dan Ni(II) sebagai media yang dapat berekasi dengan hidrogen peroksida untuk mengahasilkan reaksi Fenton. Rekasi fenton akan menghasilkan hidroksil radikal yang dapat menyebabkan peningkatan stress oksidatif sehingga menghasilkan rekatif oksigen spesies (ROS) yang berakibat pada mutasi DNA.Pada penelitian ini baik secara in vitro maupun in vivo diperoleh hasil bahwa dengan penambahan dua ion logam, Cu(II) dan Ni(II), menghasilkan efek yang supresif, artinya nilai konsentrasi 8-OHdG yang diperoleh lebih kecil dibandingkan dengan nilai masing-masing logam. Hal itu disebabkan ion logam Ni(II) akan menekan oksidasi DNA sehingga oksidasi DNA dengan ion logam Cu(II) akan terganggu. 8-OHdG terbanyak diperoleh dengan pencampuran paraquat diklorida dan ion logam Cu(II). Kajian in viro ini menggunakan kondisi inkubasi pada suhu 370C mewakili kondisi tubuh dan pH 7,4 serta 8,4 dengan waktu inkubasi 24 jam dan 6 jam. Diperoleh untuk kadar 8-OHdG dari ion logam Cu(II) dan paraquat diklorida sebesar 101,48 ppb dan 134,60 ppb. Sedangkan nilai kadar urin dan serum dari proses in vivo hari 14 dan 28 adalah 6,76 ppb& 3,48 ppb dan 1,22 ppb dan 0,76 ppb.

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Increased DNA adduct, which is 8-OHdG is influenced by the presence of xenobiotics which are toxic and carcinogenic. Xenobiotics used in this study are paraquat dichloride, known as paraquat dichloride, a group II pesticide based on WHO which has a dangerous effect because it can cause gene mutations, so it has a carcinogenic impact. Adding Cu(II) and Ni(II) metal ions as a medium can reject hydrogen peroxide to produce Fenton reactions. Fenton's reaction will produce radical hydroxyl, which can cause an increase in oxidative stress to have oxygen species (ROS), resulting in DNA mutations.

In this study, both in vitro and in vivo obtained the result that the addition of two metals, Cu(II) and Ni(II) ions, produced a suppressive effect, meaning that the 8-OHdG concentration value obtained was smaller than the respective values metal. That is because Ni(II) metal ions will suppress DNA oxidation, so DNA oxidation with Cu(II) metal will be disrupted. 8-OHdG is obtained by mixing paraquat dichloride and Cu(II). In vitro study uses incubation conditions at 370C, representing the condition of the body and pH of 7.4 and 8.4 with an incubation time of 24 hours and 6 hours. They obtained 8-OHdG levels of Cu(II) metal ions and paraquat dichloride of 101.48 ppb and 134.60 ppb. While the concentration of urine and serum from in Vivo process days 14 and 28 is 6.76 ppb & 3.48 ppb and 1.22 ppb and 0.76 ppb."

"ABSTRAKMangiferin merupakan salah satu senyawa derivat xanton yaitu C-glikosilxanton yang berpotensi dikembangkan menjadi agen pengkelat besi namun bioavailabilitas pada pemberian secara oral sangat rendah dan kelarutannya kurang baik. Preparasi mangiferin dalam nanopartikel kitosan-alginat diharapkan dapat meningkatkan bioavailabilitas mangiferin karena dengan memperkecil ukuran mangiferin akan memperbesar luas permukaan dan meningkatkan interaksi dengan pelarut sehingga kelarutan akan meningkat. Nanopartikel juga dapat menghantarkan senyawa obat dengan baik sampai ke unit-unit kecil dalam tubuh, meningkatkan distribusi, serta obat tepat target, sehingga meningkatkan efek terapetik. Tujuan penelitian ini adalah untuk mengetahui berbagai parameter farmakokinetik nanopartikel kitosan-alginat mangiferin yang diberikan secara oral pada tikus. Penelitian dilakukan pada tikus jantan Sprague-Dawley yang diberi nanopartikel kitosan-alginat mangiferin sebesar 50 mg/kgBB secara oral. Darah diambil dari vena ekor pada 0; ½; 1; 2; 3; 4; 4½; 5; 5½ dan 6 jam setelah pemberian oral. Hati dan jantung diambil pada jam ke 4 dan 6 setelah pemberian oral. Analisis kadar mangiferin pada plasma, hati dan jantung menggunakan HPLC. Parameter farmakokinetik telah dihitung. Konsentrasi maksimum nanopartikel kitosan-alginat mangiferin dalam plasma mencapai 634,65 ± 10,37 ng/mL dengan Tmax 4 jam setelah pemberian oral dan waktu paruh eliminasi (t1/2) adalah 6,45 ± 0,15 jam. Konsentrasi nanopartikel kitosan-alginat mangiferin di jantung dan di hati pada jam keempat dan keenam setelah pemberian oral berturut-turut adalah 753,16 ± 93,48 ng/mL, 1976,55 ± 40,06 ng/mL, 1998,81 ± 72,25 ng/mL, dan 3562,81 ± 189,28 ng/mL. Peningkatan kadar mangiferin pada kelompok nanopartikel kitosan-alginat mangiferin di plasma, jantung dan hati menunjukkan bentuk nanopartikel kitosan-alginat mangiferin memiliki absopsi yang lebih baik dibanding kelompok mangiferin. Preparasi nanopartikel kitosan-alginat mangiferin dapat mempengaruhi profil farmakokinetik mangiferin pada plasma dan distribusinya pada hati dan jantung tikus.

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ABSTRACTMangiferin is one of the xanthone derivative compounds, namely C-glicosylxanthones which has the potential to be developed into an iron chelating agent but the bioavailability of oral administration is very low, and its have poor solubility. The preparation of mangiferin in chitosan-alginate nanoparticles are expected to increase the bioavailability of mangiferin because by reducing particle size it will increase the surface area and increase interaction with the solvent so that solubility will increase. Nanoparticles can also deliver medicinal compounds well to small units in the body, increase distribution, and target drugs, thereby increasing therapeutic effects. The purpose of this study was to determine the various pharmacokinetic parameters of chitosan-alginate mangiferin nanoparticles given orally in rats. The study was conducted on Sprague-Dawley male rats were given 50 mg/ kgBW of chitosan-alginate mangiferin orally. Blood samples were taken from the tail vein at 0; ½; 1; 2; 3; 4; 4½; 5; 5½ and 6 hours after oral administration. Heart and liver organs are taken at the fourth and sixth hour after oral administration. Analysis of mangiferin levels in plasma, liver, and heart using HPLC. The pharmacokinetics parameters were calculated. The maximum concentration of chitosan-alginate mangiferin nanoparticles in plasma reached 634.65 ± 10.37 ng/mL with Tmax 4 hours after oral administration, and the apparent elimination half-life (t1/2) was 6,45 ± 0,15 hours. Concentrations in the heart and liver in the fourth and sixth hours after oral administration were 753,16 ± 93,48 ng/mL, 1976,55 ± 40,06 ng/mL, 1998,81 ± 72,25 ng/mL, and 3562,81 ± 189,28 ng/mL. Increased concentrations of chitosan-alginate mangiferin nanoparticles in plasma, heart, and liver showed that chitosan-alginate mangiferin nanoparticles had good absorption. Preparation of chitosan-alginate mangiferin nanoparticles can affect the pharmacokinetic profile of mangiferin in plasma and its distribution to the liver and heart of rats."

"Contents :1. Zusammenfassung und Empfehlungen2. AnlaB und Anliegen3. Das Fachgebiet4. Toxikologie in Deutschland5. Toxikologie im Ausland6. DFG-Denkschrift 1975 und ihre Folgen7. Literatur8. Anhang"

"Penelitian ini bertujuan untuk mengembangkan suatu pemodelan matematis, Physiologically-Based Pharmacokinetic (PBPK) yang dapat menggambarkan biodistribusi Nivolumab pada pasien. Penelitian ini menggunakan data biodistribusi dari 89Zr-nivolumab pada tikus humanized-Peripheral Blood Lymphocytes-Severe Combined Immunodeficiency (hu-PBL-SCID) atau tikus PBL. Kompartemen organ pada struktur pemodelan PBPK terdiri dari ruang vaskular, interstitial, serta endothelial. Parameter yang diestimasi adalah faktor modulasi laju transkapiler (MK) dan faktor modulasi laju pinositosis (F2) dari masing-masing organ, serta clearance dari plasma (CLePL). Setelah berhasil mendapatkan nilai parameter yang diestimasi, model PBPK akan ditranslasikan ke manusia untuk dianalisa nilai area di bawah kurva (AUCs) terkait toksisitas obat di dalam tubuh. Parameter yang tidak diketahui dalam model PBPK berhasil diestimasi dari data, ditunjukkan dengan visualisasi grafik dengan koefisien variasi dari parameter (%CV≤50%). Nilai parameter yang diestimasi adalah CLePL=5,56x10^-5 (%CV = 25,60%), MK=5,26x10^-1 – 4,27 (%CV=15,09% – 24,91%), dan F2=2,41x10^-2 – 4,31x10^-2 (%CV=23,84% – 29,55%) untuk hati; limpa; ginjal; dan jaringan otot. Studi simulasi menunjukkan bahwa peningkatan dosis Nivolumab yang diinjeksikan akan meningkatkan nilai AUCs toksisitas obat pada setiap organ di dalam tubuh manusia. Pemodelan matematis telah berhasil dikembangkan dan mampu menggambarkan biodistribusi dari 89Zr-Df-nivolumab pada tikus.

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This study aimed to develop a mathematical model, Physiologically-Based Pharmacokinetic (PBPK) to describe the biodistribution of Nivolumab in patients. This study used biodistribution data from 89Zr-nivolumab in humanized-Peripheral Blood Lymphocytes-Severe Combined Immunodeficiency (hu-PBL-SCID) mice or PBL mice. The organ compartments in the PBPK modeling structure consist of vascular, interstitial, and endothelial spaces. The estimated parameter were the modulation factor of transcapillary flow (MK) and modulation factor of pinocytosis rate (F2) from each organ, as well as plasma clearance (CLePL). After successfully obtaining the estimated parameter values, the PBPK model will be translated to humans to analyze the value of the Area Under the Curves (AUCs) related to drug toxicity in the body. The unknown parameters in the PBPK model was successfully estimated from the data, shown by the visualization of the graph with the coefficient of variation of the parameters (%CV≤50%). The values of the estimated parameters were CLePL=5,56x10^-5 (%CV = 25,60%), MK=5,26x10^-1 – 4,27 (%CV=15,09% – 24,91%), dan F2=2,41x10^-2 – 4,31x10^-2 (%CV=23,84% – 29,55%) for liver, spleen, kidney, and muscle. The simulation study showed that increasing the injected dose of Nivolumab will increase the value of AUCs and drug toxicity in the human body. Mathematical modeling has been successfully developed and was able to describe the biodistribution of 89Zr-Df-nivolumab in mice."

"The challenge remains to find the proper combination of these techniques in view of their respective potential, limitations, and costs, in order to pick up the right compounds quickly while keeping the risk of eliminating ‘good’ candidates as low as possible. Potential and limitations of a number of approaches to get early information on solubility and permeability, the main factors governing absorption via passive diffusion, will be discussed with practical examples.It aims at offering longlasting knowledge and stimulating food for thought. This is why its three main parts (biological, physicochemical, and computational strategies) are accompanied by two chapters which set the scene, four others which review the molecular and biological background of pharmacokinetic lead optimization, and finally two which conclude the book. "

"The profiling of ADME properties (absorption, distribution, metabolism, and excretion) is the topic of this book. In this unique work, international authorities and practicing experts from academia and industry offer state-of-the-art presentations of concepts, methods and technologies now in use or development in drug research. The biological strategies emphasized in the book include cell cultures, drug-metabolizing enzymes, transporters and plasma protein binding. The physicochemical strategies focus on artificial membrane-permeability assays, on solubility and lipophilicity and related molecular properties as factors and predictors of pharmacokinetic behavior, and on stability and solid-state properties. Computational strategies comprize the exploration of property spaces, pharmacophore searching to predict biotransformation and enzyme inhibition, and expert systems to process biopharmaceutical profiling data."

"Principles of toxicology : environmental and industrial applications, this edition provides health protection professionals as well as environmental scientists with precise, up-to-date, practical information on how to apply the science of toxicology in both the occupational and environmental setting. Through contributions from leading experts in diverse fields. Principles of toxicology, second edition features :

• - Clear explanations of the fundamentals necessary for an understanding of the effects of chemical hazards on human health and ecosystems
• - Coverage of occupational medicine and epidemiological issues
• - The manifestation of toxic agents such as metals, pesticides, organic solvents, and natural toxins
• - Special emphasis on the evaluation and control of toxic hazards
• - Specific case histories on applying risk assessment methods in the modern workplace
• - Ample figures, references, and a comprehensive glossary of toxicological terms

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"ABSTRAKPada penelitian ini dilakukan preparasi dan karakterisasi nanopartikel primakuin berbasis kitosan. Preparasi nanopartikel primakuin dilakukan dengan menggunakan metode gelasi ionik. Karakterisasi nanopartikel primakuin dilakukan untuk mengetahui distribusi ukuran partikel, zeta potensial da morfologi partikel. Selanjutnya nanopartikel primakuin dan primakuin konvensional diujikan ke tikus secara oral untuk membandingkan profil farmakokinetik keduanya. Hasil menunjukkan distribusi ukuran partikel pada 248,8 nm, dengan lebar puncak 29,61 nm, efisiensi penjerapan54,7% dan zeta potensial. Pada uji in vivo di tikus, konsentrasi primakuin dalam plasma 2-2,5 kali lebih rendah dibandingkan primakuin konvensional, tetapi 3 kali lebih tinggi di hati. Penghitungan parameter farmakokinetik menunjukkan AUC nanopartikel primakuin 3,3 kali lebih rendah dan Cmax nanopartikel primakuin 2,3 kali lebih rendah dibandingkan primakuin konvensional. Namun tidak ada perbedaan pada Tmax. Nilai ke nanopartikel primakuin lebih rendah dan t1/2 eliminasi memanjang 3 kali lipat dibandingkan primakuin konvensional. Vd nanopartikel primakuin 6,5 kali lebih besar dibandingkan primakuin konvensional. Penelitian ini menunjukkan nanopartikel primakuin terbukti berhasil meningkatkan penghantaran obat ke hati.

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ABSTRACTThe aim of this study was to prepare primaquine- loaded chitosan nanoparticles to enhance drug transport to the liver. Primaquine nanoparticles were prepared by using ionic gelation. Nanoparticles were characterized by particle size distribution, entrapment efficiency, zeta potential and morphology. Conventional primaquine and primaquine nanoparticles were administered orally to rats in order to compare the pharmacokinetic profiles. The characterization of nanoparticles exhibited a peak of particle size distribution at 248.8 nm, peak width of 29.61 nm, entrapment efficiency of 54.7%, and zeta potential of +1.4 mV. In rats, we observed 2-2.5 times smaller plasma concentrations of primaquine nanoparticles than conventional primaquine, but 3 times higher concentration in the liver. The calculation of pharmacokinetic parameters of primaquine revealed that nanoparticles have 3.3 times smaller AUC and 2.3 times smaller Cmax than conventional administration, but no different Tmax. Absorption rate constant and absorption phase half life of nanoparticles were statistically not different from conventional primaquine. Elimination rate constant and elimination phase half life of nanoparticles exceeded 3 times the values of conventional primaquine. The pharmacokinetic distribution of primaquine nanoparticles showed a 6.5 times greater volume than that of primaquine. This study exhibited that primaquine nanoparticles successfully enhanced drug transport to the liver."