| 1. |
- Ashton, M, et al.
(författare)
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Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat
- 1999
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 29:2, s. 195-204
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Tidskriftsartikel (refereegranskat)abstract
- 1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg(-1)) or i.p. (50 mg.kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95 % confidence interval: 10.4, 13.0) l.h(-1).kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) I.h(-1).kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was similar to 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8+/-2.0%) compared with the female rat (11.7+/-2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.
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| 2. |
- Asp, Vendela, et al.
(författare)
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Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
- 2010
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 40:3, s. 177-183
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Tidskriftsartikel (refereegranskat)abstract
- 1. Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. 2. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. 3. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o, p'-DDD racemate and the m,p'- and p,p'-isomers. 4. The results show small but statistically significant differences in activity of the o, p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p, p'- DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. 5. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.
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| 3. |
- Bergman, Ebba, 1977-, et al.
(författare)
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The Effect of Acute Administration of Rifampicin and Imatinib on the Enterohepatic Transport of Rosuvastatin In Vivo
- 2010
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 40:8, s. 558-568
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Tidskriftsartikel (refereegranskat)abstract
- Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80mg rosuvastatin in pigs (control group, n=2+6). The transport inhibitors, rifampicin (20mg/kg, n6) and imatinib (14mg/kg, n6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.132, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.13.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.
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| 4. |
- Bueters, Tjerk, et al.
(författare)
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Rat poorly predicts the combined non-absorbed and presystemically metabolized fractions in the human
- 2013
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 43:7, s. 607-616
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Tidskriftsartikel (refereegranskat)abstract
- 1. Intestinal loss, 1 - (F(obs)/f(H)), is the missing fraction of the dose that is unexplained by systemic clearance. Here, we investigated whether intestinal loss in rat is predictive for human, and whether intestinal metabolism explained observed differences between rat and human.2. For 81 marketed drugs, human and rat intestinal loss values were calculated from the literature and in-house sources. To examine the contribution of intestinal cytochrome P450-mediated metabolism to the high observed intestinal loss in the rat, metabolism was determined in rat and human intestinal microsomes for 15 compounds.3. Oral bioavailability poorly correlated between rat and human. Twenty-two compounds in the human and 47 compounds in the rat showed an intestinal loss of more than 20%. The intestinal availability for many compounds was higher in human than in rat. Selected compounds, however, were more stable in rat than in human intestinal microsomes.4. The rat poorly predicts the risk for intestinal loss in human; many compounds in rat had lower bioavailability than anticipated based on the hepatic clearance, but demonstrated little intestinal loss in human. This discrepancy appeared not to be caused by a higher cytochrome P450-mediated intestinal metabolism in the rat.
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| 5. |
- Bylund, Johan, et al.
(författare)
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Metabolic profiling of TRPV1 antagonists of the benzothiazole amide series : implications for in vitro genotoxicity assessment
- 2013
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 43:2, s. 201-210
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Tidskriftsartikel (refereegranskat)abstract
- 1. In vitro metabolic profiling and in vitro genotoxicity assessment are important aspects of the drug discovery program as they eliminate harmful compounds from further development. In standard in vitro genotoxicity testing, induced rat liver S9 is used as an exogenous bio-activation system for detecting promutagens. In this study we show that rat liver S9 is an insufficient system regarding the conversion of TRPV1 antagonists of the benzothiazole amide series into relevant in vivo metabolites. 2. Human and rat hepatocyte experiments demonstrated generation of an aryl amine metabolite that was subsequently N-acetylated. The hydrolyzed metabolites as well as the parent compound were also metabolized into glutathione (GSH) conjugates. Rat liver S9 exhibited a very low amide hydrolysis capacity and no formation of GSH conjugates when supplemented with NADPH and GSH. 3. The discrepancy in metabolic capability between hepatocytes and rat liver S9 led to confounding results in in vitro genotoxicity assessment for this chemical class as judged by the results of Ames test, mouse lymphoma assay, SOS/umu test and Comet assay in rat hepatocytes. 4. This study highlights the pivotal role that understanding the mechanism of metabolite formation has in interpreting as well as designing reliable and relevant in vitro genotoxicity experiments.
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| 9. |
- Ericsson, Therese, 1984, et al.
(författare)
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Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: potential implications for combination therapies.
- 2014
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 44:7, s. 615-626
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Tidskriftsartikel (refereegranskat)abstract
- 1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug–drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC–MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro–in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution.
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| 10. |
- Fagerholm, Urban, et al.
(författare)
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Comparison between lab variability and in silico prediction errors for the unbound fraction of drugs in human plasma
- 2021
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Ingår i: Xenobiotica. - : Taylor & Francis. - 0049-8254 .- 1366-5928. ; 51:10, s. 1095-1100
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Tidskriftsartikel (refereegranskat)abstract
- Variability of the unbound fraction in plasma (f(u)) between labs, methods and conditions is known to exist. Variability and uncertainty of this parameter influence predictions of the overall pharmacokinetics of drug candidates and might jeopardise safety in early clinical trials. Objectives of this study were to evaluate the variability of human in vitro f(u)-estimates between labs for a range of different drugs, and to develop and validate an in silico f(u)-prediction method and compare the results to the lab variability. A new in silico method with prediction accuracy (Q(2)) of 0.69 for log f(u) was developed. The median and maximum prediction errors were 1.9- and 92-fold, respectively. Corresponding estimates for lab variability (ratio between max and min f(u) for each compound) were 2.0- and 185-fold, respectively. Greater than 10-fold lab variability was found for 14 of 117 selected compounds. Comparisons demonstrate that in silico predictions were about as reliable as lab estimates when these have been generated during different conditions. Results propose that the new validated in silico prediction method is valuable not only for predictions at the drug design stage, but also for reducing uncertainties of f(u)-estimations and improving safety of drug candidates entering the clinical phase.
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