Metabonomics analysis of liver in rats administered with chronic low-dose acrylamide.
Abstract 1. The current study aimed to investigate the hepatotoxicity of rats administered with chronic low-dose acrylamide (AA) by using metabonomics technology on the basis of ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). A total of 40 male Wistar rats were randomly divided into the following four groups: control, low-dose AA (0.2 mg/kg bw, non-carcinogenic end-point based on the induction of morphological nerve changes in rats), middle-dose AA (1 mg/kg bw), and high-dose AA (5 mg/kg bw). The rats continuously received AA by administering it in drinking water daily for ...
Source: Xenobiotica - January 13, 2020 Category: Research Authors: Liu Y, Wang R, Zheng K, Xin Y, Jia S, Zhao X Tags: Xenobiotica Source Type: research

Modulation of ABCG2 surface expression by Rab5 and Rab21 to overcome multi drug resistance in cancer cells.
Abstract 1. Human ABCG2 is a half transporter implicated in drug efflux and development of multidrug resistance (MDR) in cancer cells. Here we present the regulatory effects of early endocytic Rab GTPases, Rab5A and Rab21 on ABCG2.2. ABCG2 was stably expressed in MCF-7 cells (MCF-7/G2). Rab5A and Rab21 was manipulated in MCF-7/G2 cells by co expression or siRNA knockdown and their effect on ABCG2 mediated drug efflux was quantified using fluorescence microscopy.3. The ectopically expressed ABCG2 was predominantly confined to the plasma membrane and was capable of drug efflux. Expression of constitutively active Ra...
Source: Xenobiotica - January 13, 2020 Category: Research Authors: Yousaf M, Ali M Tags: Xenobiotica Source Type: research

Metabolic disposition of H3B-8800, an orally available small-molecule splicing modulator, in rats, monkeys, and humans.
Abstract H3B-8800, a novel orally available modulator of the SF3b complex, which potently and preferentially kills spliceosome-mutant tumor cells, is in clinical development for the treatment of advanced myeloid malignancies. We characterized the pharmacokinetics, metabolism and disposition of H3B-8800 in rats, monkeys and humans.In vitro, H3B-8800 is a substrate of CYP3A4/5, flavin-containing monooxygenases (FMOs) and P-glycoprotein (P-gp), and showed a favorable drug-drug interaction profile as a perpetrator.Following oral dosing of 14C-H3B-8800 in bile-duct cannulated SD rats, 54.7% of the dosed radioactivity w...
Source: Xenobiotica - January 6, 2020 Category: Research Authors: Rioux N, Smith S, Colombo F, Kim A, Lai WG, Nix D, Siu YA, Schindler J, Smith PG Tags: Xenobiotica Source Type: research

In vitro sulfonation of 7-hydroxycoumarin derivatives in liver cytosol of human and six animal species.
In this study sulfonation of 7-hydroxycoumarin and 13 its derivatives were evaluated in liver cytosols of human and six animal species. 7-hydroxycoumarin and its derivatives are strongly fluorescent, and their sulfate conjugates are nonfluorescent at excitation 405 nm and emission 460 nm. A convenient fluorescence based kinetic assay of sulfonation was established.3. The sulfonation rate of most of the 7-hydroxycoumarin derivatives was low in liver cytosol of human and pig, whereas it was high with most compounds in dog and intermediate in rat, mouse, rabbit, and sheep. Sulfonation of the 7-hydroxycoumarin de...
Source: Xenobiotica - January 4, 2020 Category: Research Authors: Juvonen RO, Pentikäinen O, Huuskonen J, Timonen J, Kärkkäinen O, Heikkinen A, Fashe M, Raunio H Tags: Xenobiotica Source Type: research

Plasma concentrations of pemafibrate with co-administered drugs predicted by physiologically based pharmacokinetic modeling in virtual populations with renal/hepatic impairment.
Abstract Pharmacokinetic profiles of pemafibrate with virtual drug and/or disease interactions were assessed by creating a detailed physiologically based pharmacokinetic (PBPK) model.Passive diffusion clearance in liver was experimentally determined as 0.013 mL/min/106 human hepatocytes. In vitro intrinsic clearance values for pemafibrate by cytochromes P450 2C8, 2C9, and 3A4 were 54, 26, and 16 μL/min/mg protein, respectively. Values for the effective permeability and the intrinsic clearance of hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 were optimized in a simulator platf...
Source: Xenobiotica - January 3, 2020 Category: Research Authors: Ogawa SI, Shimizu M, Yamazaki H Tags: Xenobiotica Source Type: research

Quantitative evaluation of hepatic and intestinal induction of CYP3A in clinical practice.
Abstract 1. This is the first report quantitatively evaluating the clinical induction of CYP3A in the liver and the intestine.2. To evaluate hepatic induction, we collected literature data on endogenous biomarkers of hepatic CYP3A induction which we then used to calculate the fold-induction (inducer-mediated change in biomarker level). Literature data on decreases in the area under the curve (AUC) of alfentanil, a CYP3A substrate, caused by CYP3A inducers were also collected. We used the hepatic intrinsic clearance of alfentanil to calculate the hepatic induction ratio (inducer-mediated change in intrinsic clearan...
Source: Xenobiotica - December 30, 2019 Category: Research Authors: Tsutsui H, Kato M, Kuramoto S, Sekiguchi N, Shindoh H, Ozeki K Tags: Xenobiotica Source Type: research

Usefulness of novobiocin as a selective inhibitor of intestinal breast cancer resistance protein (Bcrp) in rats.
Abstract 1. We investigated whether novobiocin is useful for elucidating the contribution of breast cancer resistance protein (Bcrp) to intestinal absorption without affecting the activities of P-glycoprotein (P-gp), cytochrome P450 (CYP) 3A and hepatic organic anion transporting polypeptide (Oatp) in rats.2. To determine the effects of novobiocin on Bcrp, P-gp, CYP3A and Oatp activities, we used sulfasalazine, fexofenadine, bosentan and midazolam, respectively, as probe substrates. Each substrate was orally or intravenously administered to rats 15 min after oral novobiocin administration at a dose of 3&thi...
Source: Xenobiotica - December 23, 2019 Category: Research Authors: Suzuki K, Taniyama K, Aoyama T, Watanabe Y Tags: Xenobiotica Source Type: research

Withanolide A penetrates brain via intra-nasal administration and exerts neuroprotection in cerebral ischemia reperfusion injury in mice.
Discussion: Intra-nasal administration enables brain penetration of WA and allows the phytochemical to exert neuroprotective ability in the global cerebral ischemia model. PMID: 31870211 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - December 23, 2019 Category: Research Authors: Mukherjee S, Kumar G, Patnaik R Tags: Xenobiotica Source Type: research

The biotransformation of Bupleuri Radix by human gut microbiota.
In this study the main saikosaponins (SAPs) of Bupleurum (including saikosaponin a, b1, b2, c, d, f, h) and BR extract (BRE) were individually incubated with human fecal suspensions (HFS), and metabolic time courses of SAPs and their metabolites by human gut bacteria were systematically characterized.3. Deglycosylation and dehydration were the main metabolic pathways identified for SAPs including newly investigated saikosaponin f (SSf) and saikosaponin h (SSh); dehydration had not been reported previously. A total of 19 dehydrated and deglycosylated metabolites of SAPs were detected and characterized, and 10 of them were n...
Source: Xenobiotica - December 20, 2019 Category: Research Authors: Tang C, Fu Q, Chen X, Hu Y, Renaud H, Ma C, Rao T, Chen Y, Tan Z, Klaassen CD, Shi S, Guo Y Tags: Xenobiotica Source Type: research

A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes.
Abstract 1. The pathway for the transformation of the prodrug nabumetone, 4-(6-methoxynaphthalen-2-yl)butan-2-on, to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), a potent cyclooxygenase-2 inhibitor, has not yet been clarified in humans.2. To confirm the activation pathway, authentic standards of the nabumetone intermediates, 2-(6-methoxynaphthalen-2-yl)ethyl acetate (6-MNEA), 2-(6-methoxynaphthalen-2-yl)ethan-1-ol (6-MNE-ol) and 2-(6-methoxynaphthalen-2-yl)acetaldehyde (6-MN-CHO) were synthesized. High performance liquid-chromatography and gas chromatography-mass spectrometry on nabumetone oxidat...
Source: Xenobiotica - December 19, 2019 Category: Research Authors: Matsumoto K, Hasegawa T, Ohara K, Takei C, Kamei T, Koyanagi J, Takahashi T, Akimoto M Tags: Xenobiotica Source Type: research

Disposition of [14C]LY2606368 following intravenous administration in patients with advanced and/or metastatic solid tumours.
Abstract The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours.The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive meta...
Source: Xenobiotica - December 17, 2019 Category: Research Authors: Wickremsinhe ER, Hynes SM, Payne CD, Guo Y, Cassidy KC Tags: Xenobiotica Source Type: research

Characterization of osthenol metabolism in vivo and its pharmacokinetics.
Abstract 1. Osthenol, a prenylated coumarin, is a C8-prenylated derivative of umbelliferone isolated from the root of Angelica koreana and Angelica dahurica, an intermediate and is known as a major metabolite of desmethyl-osthole.2. The various pharmacological effects of osthenol have been reported. In previous studies, we investigated five hydroxylated metabolites by cytochromes P450 (CYP) and glucuronide conjugates of osthenol by uridine diphosphate-glucuronosyltransferases (UGTs). However, osthenol have very few studies have been reported on its pharmacokinetic (PK) profiling, we reported the PK parameters in m...
Source: Xenobiotica - December 17, 2019 Category: Research Authors: Cho PJ, Choi SM, Kim Y, Lee DH, Noh YE, Kim S, Kim JH, Lee T, Lee S Tags: Xenobiotica Source Type: research

Twenty years of metabonomics: so what has metabonomics done for toxicology?
Abstract In 1999 the journal Xenobiotica published a perspective article detailing the new concept of metabonomics and its application to toxicology. The approach was to apply analytical chemistry techniques, and in particular 1 H NMR spectroscopy, to profile biofluids and tissues to assess the metabolic effects of xenobiotics. Metabonomics has been shown to be sensitive not only to organ specific toxicity but also provides information on the cells, tissues and mechanisms involved, as well as their interactions with the host's sex, age, diet and environment. This review assesses the impact of metabonomics o...
Source: Xenobiotica - December 12, 2019 Category: Research Authors: Griffin JL Tags: Xenobiotica Source Type: research

Utility of hairless rats as a model for predicting transdermal pharmacokinetics in humans.
Conclusions: In vivo skin absorption data from HWY hairless rats help predict human concentration profiles for lipophilic compounds. However, the data underestimate human absorption of hydrophilic compounds. PMID: 31814485 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - December 9, 2019 Category: Research Authors: Yamamoto S, Sano N, Fukushi C, Arai Y, Karashima M, Hirabayashi H, Amano N Tags: Xenobiotica Source Type: research

Effect of treatment period with LC478, a disubstituted adamantayl derivative, on P-glycoprotein inhibition: its application to increase docetaxel absorption in rats.
Abstract Treatment periods of P-glycoprotein (P-gp) inhibitors have revealed different efficacies. We have previously reported dose-dependent inhibition of P-gp in single-treatment with LC478. However, whether repeated treatment with LC478 can inhibit P-gp even at its ineffective single-treatment dose remains unknown. Therefore, the purpose of this study was to assess the effect of repeated treatment (i.e., 7-day treatment) with LC478 on P-gp known to affect docetaxel bioavailability in rats. Effects of LC478 on P-gp mediated efflux and expression in MDCK-MDR1 cells, P-gp ATPase activity, and binding site with P-g...
Source: Xenobiotica - December 2, 2019 Category: Research Authors: Han SY, Kim ES, You BH, Chae HS, Liu Q, Chin YW, Ahn HC, Chung SJ, Lee K, Choi YH Tags: Xenobiotica Source Type: research

Comparative pharmacokinetics of quercitrin, astragalin, afzelin, and taxifolin in plasma after oral administration of Polygonum orientaleinflorescence in sham-operated and myocardial ischemia-reperfusion injury rats.
Abstract The study aimed to compare the pharmacokinetic properties of quercitrin, astragalin, afzelin, and taxifolin, four major bioactive components of Polygonum orientale inflorescence extracts, between sham-operated and myocardial ischemia-reperfusion injury (MIRI) rats. Rats were divided into two groups: MIRI model and sham-operated. The blood samples were collected according to the time schedule. The levels of quercitrin, astragalin. afzelin, and taxifolin in the plasma at designated time points were determined using an HPLC-MS/MS method. Various pharmacokinetic parameters were estimated from the plasma conce...
Source: Xenobiotica - December 2, 2019 Category: Research Authors: Zheng L, Li Y, Zhou Z, Xiang W, Gong Z, Chen S, Wang Y, Wang A, Lan Y, Li Y, Huang Y Tags: Xenobiotica Source Type: research

Prediction of circulating human metabolites of pemafibrate, a novel antidyslipidemic drug, using chimeric mice with humanized liver.
Abstract Pharmacokinetics and metabolism of recently launched antidyslipidemic drug pemafibrate ((2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) was investigated in chimeric mice with humanized liver in the present study.The plasma unbound fractions of [14C]pemafibrate in mice (0.0046-0.0048) were higher than those in monkeys and humans (0.0015-0.0022).In chimeric mice with humanized liver intravenously treated with pemafibrate at 1.0 mg/kg body weight, the pharmacokinetic parameters (CLtotal, Vss and AUC0-inf) of unbound pemafibrate in chimeric mice with human...
Source: Xenobiotica - November 25, 2019 Category: Research Authors: Ogawa SI, Uehara S, Tsunenari Y, Kawai H, Suemizu H, Yamazaki H Tags: Xenobiotica Source Type: research

Intrinsic clearance rate of O-desmethyltramadol (M1) by glucuronide conjugation and phase I metabolism by feline, canine and common brush-tailed possum microsomes.
This study indicates that M1 likely undergoes in vitro phase II glucuronidation by canine and common brush-tailed possum microsomes and, to a minor extent, by feline microsomes. The rate of depletion of M1 by phase I metabolism was also undertaken. When incubated with phase I co-factors and common brush-tailed possum microsomes or canine microsomes, M1 had an in vitro Clint of 47.6 and 22.8 μL/min/mg microsomal protein, respectively. However, due to a lack of CYP2B-like activity in the feline liver, unsurprisingly, M1 did not deplete when incubated with feline microsomes. Consequently, major M1 elimination pathwa...
Source: Xenobiotica - November 22, 2019 Category: Research Authors: Izes AM, Kimble B, Govendir M Tags: Xenobiotica Source Type: research

Relevance of preclinical rodent pharmacokinetics in the selection of a companion antibiotic for combining with beta-lactamase inhibitor.
Abstract 1. Recent approvals of β-lactamase inhibitor (BLI) drug in combination with cephalosporins/penems have provided the right impetus for novel BLIs. One important research question, hitherto not addressed, is pertaining to the relevance of preclinical pharmacokinetics for pairing the antibiotic with existing/novel BLI.2. Two BLI combination drugs: a) approved (i.e., ceftazidime/avibactam); b) clinical development (i.e., cefepime/zidebactam) were explored to provide insights to address the research question.3. Individual intravenous dosing of ceftazidime, avibactam, cefepime and zidebactam was done at 1&...
Source: Xenobiotica - November 22, 2019 Category: Research Authors: Giri P, Delvadia P, Ladani MK, Prajapati N, Joshi V, Giri S, Patel N, Jain MR, Srinivas NR Tags: Xenobiotica Source Type: research

Liver metabolomic characterization of Sophora flavescens alcohol extract-induced hepatotoxicity in rats through UPLC/LTQ-Orbitrap mass spectrometry.
This study aimed to observe the influence of Sophora flavescens alcohol extract (SFAE) on hepatic metabolic profiling in rats to explore the possible mechanism of hepatotoxicity induced by S. flavescens.Male Sprague-Dawley rats were randomly divided into three groups (n = 6 in each group) and administered with SFAE at different doses of 0, 1.25 and 2.5 g/kg for two weeks. Ultra-performance liquid chromatography-high resolution mass spectrometry was utilized to detect the change in the metabolites in rat liver. Principal component analysis and orthogonal partial least squares discriminant analysis were ...
Source: Xenobiotica - November 20, 2019 Category: Research Authors: Jiang P, Sun Y, Cheng N Tags: Xenobiotica Source Type: research

In Vitro Metabolism of Imidacloprid and Acetamiprid in Rainbow Trout and Rat.
Abstract 1. Providing an alternative to pyrethroids, organophosphates, and carbamates, the neonicotinoids are now the most widely used insecticides in the world. They are water soluble and relatively stable in soil and water which allows for run-off through surface waters and thus potentially impacting aquatic species and environments.2. While the mammalian metabolism of neonicotinoids has been studied extensively, there is a lack of understanding of their metabolism in fish species. The current study constitutes the first report of the metabolism of imidacloprid (IMI) and acetamiprid (AC) in rainbow trout.3. Form...
Source: Xenobiotica - November 14, 2019 Category: Research Authors: Kolanczyk RC, Tapper MA, Sheedy BR, Serrano JA Tags: Xenobiotica Source Type: research

A novel Css-MRTpo approach to simulate oral plasma concentration-time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite in humans using chimeric mice with humanized livers.
Abstract 1. A Css-MRTpo superposition method was devised to predict (retrospectively) oral plasma concentration-time profiles of PF-04937319 and its MIST-related metabolite, M1, in humans using chimeric mice with humanized liver.2. Original PK data were taken from a published report in which PF-04937319 and M1 were given to chimeric mice orally and/or intravenously. Human CL and Vss were predicted by single-species allometry and MRTiv,pred were calculated as Vss,pred/CL,pred. MRTpo,human were assumed to be MRTiv,pred plus MAT or mean metabolite formation time (MFT). Human Css was calculated by dividing the correct...
Source: Xenobiotica - November 13, 2019 Category: Research Authors: Kamimura H, Uehara S, Suemizu H Tags: Xenobiotica Source Type: research

The impact of assay recovery on the apparent permeability, a function of lysosomal trapping.
Abstract 1. In vitro permeability assessment tools, like PAMPA, Caco-2, and MDCK, are frequently used to assess permeability and provide input in to various classification systems. Frequently, the measured recovery values in permeability assays are poor. Poor recovery may be a result of lysosomal trapping of compound. It was hypothesized that a relationship existed between diminished assay recovery of compound due to lysosomal trapping and underestimation of the Papp value.2. To examine this hypothesis, a series of experiments were conducted measuring cellular accumulation, percent recovery, and permeability in th...
Source: Xenobiotica - November 8, 2019 Category: Research Authors: Bednarczyk D, Sanghvi MV Tags: Xenobiotica Source Type: research

Metabolism of desloratadine by chimeric TK-NOG mice transplanted with human hepatocytes.
Abstract 1. Desloratadine is an antiallergic drug with species-dependent metabolic profiles in mice, rats, monkeys, and humans. We investigated whether humanized-liver mice could reproduce the reported human-specific in vivo metabolic profile for desloratadine in terms of the formation of 3-hydroxydesloratadine and its O-glucuronide.2. Hepatocytes prepared from humans and humanized-liver mice both preferentially catalyzed the formation of 3-hydroxydesloratadine and its O-glucuronide in vitro.3. After a single oral administration of desloratadine, plasma levels of desloratadine and its metabolites (3-hydroxydeslora...
Source: Xenobiotica - November 5, 2019 Category: Research Authors: Uehara S, Yoneda N, Higuchi Y, Yoneda N, Yamazaki H, Suemizu H Tags: Xenobiotica Source Type: research

Toxicokinetics of perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), and perfluorodecanoic acid (PFDA) in male and female Hsd:Sprague Dawley SD rats following intravenous or gavage administration.
Abstract 1. Poly- and perfluorinated alkyl substances (PFAS) are environmentally persistent chemicals associated with many adverse health outcomes. The National Toxicology Program evaluated the toxicokinetics (TK) of several PFAS to provide context for toxicologic findings.2. Plasma TK parameters and tissue (liver, kidney, brain) concentrations are reported for perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), or perfluorodecanoic acid (PFDA) after single-dose administration in male and female Hsd:Sprague-Dawley ® (SD) rats.3. Generally, longer Tmax and elimination half-lives, and slower clearance...
Source: Xenobiotica - November 4, 2019 Category: Research Authors: Dzierlenga AL, Robinson VG, Waidyanatha S, DeVito MJ, Eifrid MA, Gibbs ST, Granville CA, Blystone CR Tags: Xenobiotica Source Type: research

Expression levels of microRNAs that are potential cytochrome P450 regulators in cynomolgus macaques.
Abstract 1. Although the cynomolgus macaque is an important non-human primate species used in drug metabolism studies, cynomolgus macaque microRNA expressions have not been fully investigated.2. The expressions of 11 cynomolgus microRNAs, all orthologues of P450 regulators in humans, were measured by quantitative polymerase chain reaction in adrenal gland, brain, heart, jejunum, kidney, liver, ovary, testis, and uterus. mfa-miR-122 and mfa-miR-192, potentially important biomarkers for liver toxicity, were also analysed.3. Several cynomolgus microRNAs showed preferential tissue expressions: mfa-miR-1 in heart, mfa-...
Source: Xenobiotica - November 4, 2019 Category: Research Authors: Uno Y, Yamazaki H Tags: Xenobiotica Source Type: research

Reducing Risk in Thiopurine Therapy.
Abstract The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN...
Source: Xenobiotica - November 4, 2019 Category: Research Authors: Marinaki A, Arenas-Hernandez M Tags: Xenobiotica Source Type: research

Capillary microsampling in mice: Effective way to move from sparse sampling to serial sampling in pharmacokinetic profiling.
Abstract 1. Pharmacokinetic studies are an integral part of drug discovery and development. Mice are the commonly used species for pharmacokinetics studies during early discovery studies. Conventionally, composite PK profiles are obtained from mice studies due to the physiological limitations of the total blood volume that can be drawn over a certain period. 2. With advancements in bioanalytical instrumentation and in blood sampling techniques, analysis with small volume (
Source: Xenobiotica - October 22, 2019 Category: Research Authors: Raje AA, Mahajan V, Pathade VV, Joshi K, Gavali A, Gaur A, Kandikere V Tags: Xenobiotica Source Type: research

Evaluation of mRNA expression of drug-metabolizing enzymes in acetaminophen-induced hepatotoxicity using a three-dimensional hepatocyte culture system.
In conclusion, ROS may induce the mRNA expression of nuclear receptors and promote the transcription of drug-metabolizing enzymes in the in vitro model of APAP-induced hepatotoxicity. PMID: 31631733 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - October 21, 2019 Category: Research Authors: Taniguchi M, Miyamoto H, Tokunaga A, Fumoto S, Tanaka T, Nishida K Tags: Xenobiotica Source Type: research

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS.
In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil. 2. The peak concentration (Cmax) and the area under plasma concentration-time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were...
Source: Xenobiotica - October 21, 2019 Category: Research Authors: Yao H, Wang C, Lu W, Li W, Jing W, Zhang J, Yang G, Zeng A Tags: Xenobiotica Source Type: research

PREFACE for the special issue of xenobiotica on "pharmacogenetics of drug metabolism".
PREFACE for the special issue of xenobiotica on "pharmacogenetics of drug metabolism". Xenobiotica. 2019 Oct 18;:1-4 Authors: Mitchell S, Steventon G PMID: 31625424 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - October 18, 2019 Category: Research Authors: Mitchell S, Steventon G Tags: Xenobiotica Source Type: research

Metabolism and Disposition of 2-Hydroxy-4-Methoxybenzophenone, a Sunscreen Ingredient, in Harlan Sprague Dawley Rats and B6C3F1/N Mice; a Species and Route Comparison.
Abstract 1. 2-Hydroxy-4-methoxybenzophenone (HMB) is a common ingredient in personal care products and used as an UV stabilizer. In these studies, disposition and metabolism of [14C]HMB in rats and mice was assessed following single gavage administration (10, 100, or 500 mg/kg), single IV administration (10 mg/kg), or dermal application (0.1, 1, 10, or 15 mg/kg). 2. Following gavage administration, [14C]HMB was well absorbed and excreted mainly in urine (39-57%) and feces (24-42%) with no apparent difference between doses, species or sexes. Distribution of HMB in tissues was minimal in rats (0.36%) and mice (
Source: Xenobiotica - October 15, 2019 Category: Research Authors: Mutlu E, Garner CE, Wegerski CJ, McDonald JD, McIntyre BS, Doyle-Eisele M, Waidyanatha S Tags: Xenobiotica Source Type: research

Effects of sulfotanshinone sodium injection on the pharmacokinetics and pharmacodynamics of warfarin in rats in vivo.
This study was to explore the effects of sulfotanshinone sodium injection (SSI) on the pharmacokinetics and pharmacodynamics of warfarin in rats. 2. The studies of single dose and multiple dose of warfarin were designed to assess the interaction between warfarin and SSI. Rats were divided into different groups randomly and administered with warfarin in the absence or presence of SSI. Prothrombin time (PT) and activated partial thromboplastin time (APTT) values were detected by blood coagulation analyzer, and international normalized ratio (INR) values were calculated. Plasma concentrations of warfarin enantiomers were dete...
Source: Xenobiotica - October 14, 2019 Category: Research Authors: Shi Y, Zhang W, Jiang M, Huang L, Zhou Y, Chen J, Liu D, Liu G, Dong M Tags: Xenobiotica Source Type: research

Is Genetic Variability in Carboxylesterase-1 and Carboxylesterase-2 Drug Metabolism an Important Component of Personalized Medicine?
Abstract The carboxylesterase drug hydrolysis pathway has been used extensively to improve the oral availability of drugs under the assumption that the high capacity and low substrate specificity of hydrolytic enzymes would ensure rapid, complete, and consistent conversion of prodrugs to their active metabolite. However, a growing body of literature indicates that drug hydrolysis is usually catalyzed by one primary enzyme, either carboxylesterase-1 or carboxlylesterase-2, and that there is wide variability in enzyme activity affecting the metabolism of prodrugs to their active metabolites. This review identifies c...
Source: Xenobiotica - October 11, 2019 Category: Research Authors: Laizure SC, Parker RB Tags: Xenobiotica Source Type: research

Temsirolimus Metabolic Pathways Revisited.
Abstract 1. Temsirolimus, a derivative of sirolimus, exhibits potent antitumor properties. It was the goal of this study to identify yet unknown temsirolimus metabolites generated after incubation with human liver microsomes. Previously, 23-hydroxy-, 24-hydroxy, 12-hydroxy, hydroxy-piperidine and 27-O-desmethyl temsirolimus had been described. 2. Metabolite strutures were identified using high-resolution mass spectrometry, MS/iontrap (MSn) and comparison of fragmentation patterns of the metabolites with those of temsirolimus and other known sirolimus derivatives. Moreover, enzyme kinetic parameters of temsirolimus...
Source: Xenobiotica - October 9, 2019 Category: Research Authors: Shokati T, Hartmann M, Davari B, Klawitter J, Klawitter J, Christians U Tags: Xenobiotica Source Type: research

Structure-activity relationship and in vitro inhibition of human CYP2A6 and CYP2A13 by flavonoids.
This study demonstrates the inhibition activity of kaempferol and myricetin and the structure-function relationship of these two flavonoid and previously isolated flavonoids from Vernonia cinerea and Pluchea indica against both enzymes. 3. Kaempferol could inhibit CYP2A6 with Kic value of 1.77 ± 0.47 µM while inhibit CYP2A13 with Kic value of 0.12 ± 0.01 µM. Myricetin could inhibit CYP2A6 with Kic value of 4.06 ± 0.52 µM while inhibit CYP2A13 with Kic value of 1.88 ± 0.03 µM. 4. Molecular docking indicated that CYP2A...
Source: Xenobiotica - October 3, 2019 Category: Research Authors: Boonruang S, Prakobsri K, Pouyfung P, Prasopthum A, Rongnoparut P, Sarapusit S Tags: Xenobiotica Source Type: research

Effect of cyclosporine A and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation.
This study aimed to identify the factors causing the variation of voriconazole concentration in patients with allogeneic hematopoietic stem cell transplantation. 2. The data of patients was collected, including clinical characteristics and voriconazole concentrations. A total of 5 single nucleotide polymorphisms of 3 candidate genes (CYP2C19, ABCC2, ABCG2) related to voriconazole metabolism were genotyped by MassArray method. The correlation between polymorphisms and voriconazole concentration was analyzed. 3. A total of 244 voriconazole concentrations of 43 patients were included in this study. The voriconazole concentrat...
Source: Xenobiotica - October 1, 2019 Category: Research Authors: Zeng G, Shi L, Li H, Wang L, Zhu M, Luo J, Zhang Z Tags: Xenobiotica Source Type: research

Hepatocyte Spheroids as a Viable in vitro Model for Recapitulation of Complex in vivo Metabolism Pathways of Loratadine in Humans.
In conclusion, hepatocyte spheroid were capable of recapitulating the inter-species differences in metabolism between human and rat for LOR, therefore, it may represent a viable model for studying complex metabolic pathways. PMID: 31566996 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - September 30, 2019 Category: Research Authors: Chacko SA, Ly VT, Christopher LJ, Gan J Tags: Xenobiotica Source Type: research

Effects of atorvastatin on pharmacokinetics of amlodipine in rats and its potential mechanism.
This study investigates the effects of atorvastatin on the pharmacokinetics of ALDP in rats and clarifies its main mechanism. 3. The pharmacokinetic profiles of oral administration of ALDP (1 mg/kg) in Sprague-Dawley rats, with or without pretreatment of atorvastatin (1.5 mg/kg/day for 7 days) were investigated. The effects of atorvastatin on the metabolism of ALDP were also investigated using rat liver microsomes. 4. The results showed that atorvastatin could significantly increase the peak plasma concentration (from 18.28 ± 2.65 to 24.13 ± 1.96 ng/mL), and de...
Source: Xenobiotica - September 26, 2019 Category: Research Authors: Yang J, Li Y, Li Y, Rui X, Du M, Wang Z Tags: Xenobiotica Source Type: research

Circadian clock-controlled drug metabolism and transport.
Abstract 1. Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and pharmacokinetics. 2. Time-dependent pharmacokinetics (also known as chronopharmacokinetics) is associated with time-varying drug effects and toxicity. 3. This review summarizes drug-metabolizing enzymes and transporters with rhythmic expressions in the liver, intestine and/or kidney. Correlations of these diurnal proteins with circadian variations in drug exposure and effects/toxicity are covered. We also discuss the molecular mechanisms for circadian control of e...
Source: Xenobiotica - September 23, 2019 Category: Research Authors: Zhao M, Xing H, Chen M, Dong D, Wu B Tags: Xenobiotica Source Type: research

Influence of glycyrrhetinic acid on the pharmacokinetics of warfarin in rats.
Abstract 1. Combination of different drugs has been widely applied in clinics in China. Both glycyrrhetinic acid (GA) and warfarin possess various pharmacological activities, the co-administration of them is becoming popular. However, the herb-drug interaction between GA and warfarin is still unknown. 2. The herb-drug interaction between GA and warfarin in vivo and in vitro was studied, to clarify the effect of GA on the pharmacokinetics of warfarin and its main mechanism. 3. The pharmacokinetics of intragastric administered warfarin (0.5 mg/kg) with or without GA pretreatment (100 mg/kg/day, seven d...
Source: Xenobiotica - September 21, 2019 Category: Research Authors: Song J, Dai H, Zhang H, Liu Y, Zhang W Tags: Xenobiotica Source Type: research

Optimization of initial dosing scheme of tacrolimus in pediatric refractory nephrotic syndrome patients based on CYP3A5 genotype and coadministration with wuzhi-capsule.
Abstract 1. The present study aimed to optimize the tacrolimus initial dosing scheme in pediatric refractory nephrotic syndrome patients based on population pharmacokinetics and pharmacogenomics. 2. Demographic characteristics, concomitant medication, laboratory data, pharmacogenomics were collected to build model and Monte Carlo was used to simulate the optimization of initial dosing scheme. 3. Weight, the polymorphisms of CYP3A5, and concomitant medication of wuzhi-capsule were included into the covariates affecting tacrolimus clearance. In addition, with the same weight, there was difference in tacrolimus clear...
Source: Xenobiotica - September 18, 2019 Category: Research Authors: Chen X, Wang DD, Xu H, Li ZP Tags: Xenobiotica Source Type: research

A hybrid model to evaluate the impact of active uptake transport on hepatic distribution of atorvastatin in rats.
Abstract Mathematical modelling remains a useful tool to study the impact of transporters on overall and intracellular drug disposition. The impact of organic anion transporter protein mediated uptake on atorvastatin systemic and intracellular pharmacokinetics, specifically distribution volume, was studied in rats with mathematical modelling and conducting in vivo pharmacokinetic studies for atorvastatin in presence and absence of rifampicin. A previously developed 5-compartment explicit membrane model for the liver was combined with a compartmental model to develop a semi-physiological hybrid model for atorvastat...
Source: Xenobiotica - September 18, 2019 Category: Research Authors: Kulkarni P, Korzekwa K, Nagar S Tags: Xenobiotica Source Type: research

Plasma and cerebrospinal fluid pharmacokinetics of hydroxysafflor yellow A in patients with traumatic brain injury after intravenous administration of Xuebijing using LC-MS/MS method.
This study provides evidence for better understanding the pharmacokinetics and potential for clinical guidance of XBJ for TBI treatment. PMID: 31524030 [PubMed - as supplied by publisher] (Source: Xenobiotica)
Source: Xenobiotica - September 16, 2019 Category: Research Authors: Sheng C, Peng W, Xia Z, Wang Y Tags: Xenobiotica Source Type: research

Pharmacogenetics and drug metabolism. Historical perspective and appraisal.
Abstract The events leading up to the discovery of genetically-controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field. The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a ...
Source: Xenobiotica - September 16, 2019 Category: Research Authors: Smith RL, Mitchell SC Tags: Xenobiotica Source Type: research

The characteristics and mechanism of co-administration of lovastatin solid dispersion with kaempferol to increase oral bioavailability.
Abstract Lovastatin shows low bioavailability (lower than 5%) after oral administration because of the poor aqueous solubility and widely metabolized by CYP3A4. Lovastatin solid dispersion was designed to enhance the dissolution. The in vitro intestinal absorption study indicated an increase in the apparent permeability of different intestinal segments compared with crude lovastatin. In the range of 12.5-50 μg/ml, the absorption of both lovastatin and lovastatin solid dispersion were found to be a passive process in rat's jejunum and ileum, but not endocytosis process. CYP3A4 inhibitor (ketoconazole) sig...
Source: Xenobiotica - September 11, 2019 Category: Research Authors: Li J, Di L, Cheng X, Ji W, Piao H, Cheng G, Zou M Tags: Xenobiotica Source Type: research

Predicting successful/unsuccessful extrapolation for in vivo total clearance of model compounds with a variety of hepatic intrinsic metabolism and protein bindings in humans from pharmacokinetic data using chimeric mice with humanised liver.
Abstract 1. Immunodeficient chimeric mice with humanised liver have been useful in predicting total clearance values of drugs in humans. However, their usefulness may currently be limited for specific compounds with interspecies differences. 2. In vivo total clearance and in vitro hepatic intrinsic clearance values of 16 model compounds were determined in control/humanised-liver mice and in mouse and human hepatocytes, respectively, for extrapolating the total clearance values of compounds in humans. 3. The predictability of in vivo total clearance values of 11 model compounds in humans was adequate using pharmaco...
Source: Xenobiotica - September 6, 2019 Category: Research Authors: Sawada T, Yamaura Y, Higuchi S, Imawaka H, Yamazaki H Tags: Xenobiotica Source Type: research

Effects of antibiotics on the pharmacokinetics of indoxyl sulfate, a nephro-cardiovascular toxin.
This study investigated the effects of ciprofloxacin, cefuroxime, cefotaxime, cefazolin and ofloxacin on the intravenous pharmacokinetics of IS in rats. IS was intravenously injected with and without each individual antibiotics, and the concentrations of IS in serum and lysate were determined by HPLC. 3. The results showed that ciprofloxacin significantly increased AUC0-t and T1/2 of IS by 272% and 491%, respectively, and decreased the clearance by 71%. However, ofloxacin, cefuroxime, cefotaxime and cefazolin did not alter the pharmacokinetics of IS. Furthermore, cell line study showed that ciprofloxacin inhibited the OAT3...
Source: Xenobiotica - August 26, 2019 Category: Research Authors: Luo SS, Yu CP, Hsieh YW, Chao PL, Sweet DH, Hou YC, Lin SP Tags: Xenobiotica Source Type: research

Metabolism and Disposition of the SGLT2 Inhibitor Bexagliflozin in Rats, Monkeys and Humans.
Abstract 1. Bexagliflozin is a C-aryl glucoside inhibitor of human sodium-glucose linked transporter 2 (SGLT2) that undergoes oxidation and glucuronidation to form six principal metabolites in humans. 2. In vitro metabolism by human liver microsomes and recombinant enzymes is primarily mediated by CYP3A4 and UGT1A9. Three major oxidation products and three major glucuronides have been identified in vivo. Metabolism by rats is mostly by oxidation whereas metabolism by monkeys and humans is mostly by glucuronidation. Metabolism by monkeys closely resembles metabolism by humans and all metabolites found in humans are...
Source: Xenobiotica - August 21, 2019 Category: Research Authors: Zhang W, Li X, Ding H, Lu Y, Stilwell GE, Halvorsen YD, Welihinda A Tags: Xenobiotica Source Type: research

Pharmacokinetics and lung distribution of macrolide antibiotics in sepsis model rats.
Abstract 1. Recent studies have shown azithromycin-specific clinical efficacy against macrolide-resistant strains of Streptococcus pneumoniae, despite the low susceptibility of the bacteria in vitro. This discrepancy complicates dosing and selection for treatment of macrolide-resistant strains. Although phagocyte delivery of azithromycin to inflamed tissues is considered a possible factor for clinical efficacy, there is a lack of sufficient evidence, and other pharmacokinetic factors under systemic inflammation may contribute. 2. The concentrations of azithromycin, clarithromycin, and erythromycin in the plasma an...
Source: Xenobiotica - August 19, 2019 Category: Research Authors: Kobuchi S, Fujita A, Kato A, Kobayashi H, Ito Y, Sakaeda T Tags: Xenobiotica Source Type: research