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  • 1. Ashton, M
    et al.
    Johansson, L
    Thornqvist, A S
    Svensson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat1999In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 29, no 2, p. 195-204Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Asp, Vendela
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Cantillana, Tatiana
    Bergman, Åke
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells2010In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 3, p. 177-183Article in journal (Refereed)
    Abstract [en]

    Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. 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. 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. 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. 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.

  • 3.
    Bergman, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Effect of Acute Administration of Rifampicin and Imatinib on the Enterohepatic Transport of Rosuvastatin In Vivo2010In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 8, p. 558-568Article in journal (Refereed)
    Abstract [en]

    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.

  • 4. Bueters, Tjerk
    et al.
    Juric, Sanja
    Sohlenius-Sternbeck, Anna-Karin
    Hu, Yin
    Bylund, Johan
    DMPK, Innovative Medicines CNS&Pain, AstraZeneca R&D, Södertälje , Sweden .
    Rat poorly predicts the combined non-absorbed and presystemically metabolized fractions in the human2013In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 43, no 7, p. 607-616Article in journal (Refereed)
    Abstract [en]

     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.

  • 5.
    Bylund, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Petersson, Carl
    Lindgren, Anders
    Olofsson, Susanne
    Czene, Stefan
    Metabolic profiling of TRPV1 antagonists of the benzothiazole amide series: implications for in vitro genotoxicity assessment2013In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 43, no 2, p. 201-210Article in journal (Refereed)
    Abstract [en]

    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.

  • 6. Juric, Sanja
    et al.
    Lundquist, Patrik
    DMPK.
    Hu, Yin
    Juréus, Anna
    Sohlenius-Sternbeck, Anna-Karin
    The utility of cold-preserved human hepatocytes in studies on cytochrome P450 induction and hepatic drug transport2013In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 43, no 9, p. 785-791Article in journal (Refereed)
    Abstract [en]

    Human hepatocytes that had been cold-preserved in SureTran(TM) matrix (Abcellute Ltd, Cardiff, UK) were used for studies on cell viability, cytochrome P450 (CYP) 3A4, 2B6 and 1A2 induction and hepatic drug transporters. It has recently been shown that basal CYP activities are maintained in cold-preserved hepatocytes (Palmgren et al., 2012). After 5 d of cold preservation, the viability was still more than 70%, and after 8 d it was around 60%. In hepatocytes that had been cold-preserved for 3 d, the activity of CYP3A4 was induced around 15-fold upon treatment with 8 µM rifampicin for 72 h. For CYP2B6, the activity was induced 4- to 16-fold in hepatocytes that had been cold-preserved for 3 d and thereafter treated with 1 mM phenobarbital for 72 h. The activity of CYP1A2 was low and close to the limit of detection in non-treated cells that had been cold-preserved for up to 3 d, while the activity increased in cells treated with 0.3-25 µM β-naphthoflavone for 72 h. CYP3A4, 2B6 and 1A2 mRNA levels were only determined with hepatocytes from one donor and increased upon treatment with the inducers. Hepatic uptakes of estrone-3-sulfate, taurocholate, ipratropium and rosuvastatin were stable in human hepatocytes that had been cold-preserved for up to 2 d. In summary, cold-preserved human hepatocytes demonstrate retained viability and can advantageously be used for in vitro induction studies and for studies of hepatic uptake transporters.

  • 7.
    Lennernäs, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal permeability and its relevance for absorption and elimination2007In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 37, no 10-11, p. 1015-1051Article in journal (Refereed)
    Abstract [en]

    Human jejunal permeability (P-eff) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P-eff are often based on multiple parallel transport processes. Site-specific jejunal P-eff cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P-eff > 1. 5 x 10(-4) cm s(-1) will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. > 85%) mediated by passive transcellular diffusion. The determined jejunal P-eff for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.

  • 8.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Åberg, Annica Tevell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    High-resolution mass spectrometric investigation of the phase I and II metabolites of finasteride in pig plasma, urine and bile2014In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 44, no 6, p. 498-510Article in journal (Refereed)
    Abstract [en]

    1. The metabolite profile of the 5 alpha-reductase type II inhibitor finasteride has been studied in pig plasma, urine and bile using high-resolution mass spectrometry. The porcine biotransformation products were compared to those formed by human liver microsomes and to literature data of recently identified human in vivo metabolites. The objective of this study was to gain further evidence for the validity of using pigs for advanced, invasive drug-drug interaction studies that are not possible to perform in humans. 2. The use of high-resolution mass spectrometry with accurate mass measurements enabled identification of the metabolites by calculation of their elemental compositions as well as their fragmentation patterns. 3. There was an excellent match between the porcine and human metabolic profiles, corroborating the pig as a model of human drug metabolism. The glucuronides of the two recently described human hydroxylated metabolites MX and MY and the carboxylated metabolite M3 were identified as the major biotransformation products of finasteride in pig urine and bile. 4. Furthermore, the CYP enzymes involved in the formation of the hydroxylated metabolites were characterized. Human recombinant CYP3A4 could produce the two major hydroxylated metabolites MX and MY, whereas human recombinant CYP2D6 formed MY only.

  • 9.
    Miyake, Masateru
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Otsuka Pharmaceut Co Ltd, Formulat Res Inst, Bioavailabil Res Project, Tokushima, Japan..
    Nakai, Daisuke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of proinflammatory cytokine IL-6 on efflux transport of rebamipide in Caco-2 cells2017In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 47, no 9, p. 821-824Article in journal (Refereed)
    Abstract [en]

    1. Effect of IL-6, a pro-inflammatory cytokine, on efflux transport of rebamipide, an antiulcer drug, was investigated in Caco-2 cells. 2. Rebamipide had a greater basal-to-apical than apical-to-basal transport rate. Efflux transport of rebamipide was inhibited by cyclosporine A, a P-gp inhibitor, and probenecid, which is a general MRP inhibitor, but not by Ko143, a BCRP inhibitor. 3. By the addition of IL-6, mannitol transport was slightly increased in a concentration-dependent manner in both directions of absorption and efflux. The addition of IL-6 did not change efflux transport of rebamipide even though efflux transport of digoxin, a typical substrate of P-gp, was significantly decreased by the addition of IL-6, indicating decrease of the function of P-gp. 4. Therefore, it was suggested that increase of MRP(s)-mediated transport compensates for the decrease of P-gp mediated transport of rebamipide. These findings suggested that rebamipide absorption is unlikely to be changed in IBD patients.

  • 10.
    Rydevik, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Thevis, Mario
    Krug, Oliver
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    The fungus Cunninghamella elegans can produce human and equine metabolites of selective androgen receptor modulators (SARMs)2013In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 43, no 5, p. 409-420Article in journal (Refereed)
    Abstract [en]

    1. Selective androgen receptor modulators (SARMs) are a group of substances that have potential to be used as doping agents in sports. Being a relatively new group not available on the open market means that no reference materials are commercially available for the main metabolites. In the presented study, the in vitro metabolism of SARMs by the fungus Cunninghamella elegans has been investigated with the purpose of finding out if it can produce relevant human and equine metabolites.

    2. Three different SARMs, S1, S4 and S24, were incubated for 5 days with C. elegans. The samples were analysed both with and without sample pretreatment using ultra performance liquid chromatography coupled to high resolution mass spectrometry.

    3. All the important phase I and some phase II metabolites from human and horse were formed by the fungus. They were formed through reactions such as hydroxylation, deacetylation, O-dephenylation, nitro-reduction, acetylation and sulfonation.

    4. The study showed that the fungus produced relevant metabolites of the SARMs and thus can be used to mimic mammalian metabolism. Furthermore, it has the potential to be used for future production of reference material.

  • 11. Sohlenius-Sternbeck, Anna-Karin
    et al.
    Fagerholm, Urban
    Bylund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The volume of distribution is an indicator of poor in vitro-in vivo extrapolation of clearance for acidic drugs in the rat2013In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 43, no 8, p. 671-678Article in journal (Refereed)
    Abstract [en]

     1. We applied the regression offset approach to predict rat in vivo intrinsic clearance (CL(int)) for 54 new chemical acid entities with high plasma protein binding values and low renal clearance (CL). The prediction success was correlated to volume of distribution (V(d)), molecular weight (Mw) and CL.

    2. A correlation between poor in vitro-in vivo extrapolation (IVIVE) and V(d) values distinct from the V(d) of albumin (0.1-0.2 L/kg) was revealed. For compounds with a V(d) value above 0.5 L/kg, 0% of the predictions of in vivo CL(int) was within twofold of the observed value, compared to 69% for compounds with a V(d) value below 0.5 L/kg.

    3.  Compounds with a Mw below 450 g/mol demonstrated more accurate in vivo CL(int) predictions than compounds with a Mw above 450 g/mol, i.e. 63% compared to 21% within twofold. For compounds with in vivo CL below 30% of the liver blood flow (LBF), 53% of the predictions was within twofold of the observed value, compared to 0% for compounds with CL above 30% of the LBF.

    4. We show that accurate IVIVE for acidic compounds with high plasma protein binding and low renal CL can be associated with a low V(d) (i.e. around the V(d) of albumin) and with a low in vivo CL, and that Mw is an important optimization parameter for pharmacokinetic. This study also further demonstrates the advantages of the application of the regression method for identifying cases when metabolic CL is not the single major elimination pathway.

  • 12. Sohlenius-Sternbeck, Anna-Karin
    et al.
    Jones, Christopher
    Ferguson, Douglas
    Middleton, Brian J.
    Projean, Denis
    Floby, Eva
    Bylund, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Afzelius, Lovisa
    Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes2012In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 42, no 9, p. 841-853Article in journal (Refereed)
    Abstract [en]

    1. Systematic under-prediction of clearance is frequently associated with in vitro kinetic data when extrapolated using physiological scaling factors, appropriate binding parameters and the well-stirred model. The present study describes a method of removing this systematic bias through application of empirical correction factors derived from regression analyses applied to the in vitro and in vivo data for a defined set of reference compounds.

    2. Linear regression lines were established with in vivo intrinsic clearance (CLint), derived from in vivo clearance data and scaled in vitro intrinsic clearance from isolated hepatocyte incubations. The scaled CLint was empirically corrected to a predicted in vivo CLint using the slope and intercept from a uniform weighted linear regression applied to the in vitro to in vivo extrapolation.

    3. Cross validation of human data demonstrated that 66% of the reference compounds had a predicted in vivo CLint within two-fold of the observed value. The average absolute fold error (AAFE) for the in vivo CLint predictions was 1.90. For rat, 54% of the compounds had a predicted value within two-fold of the observed and the AAFE was 1.98.

    4. Three AstraZeneca projects are used to exemplify how a two-sided prediction interval, applied to the rat regression corrected reference data, can form the basis for assessing the likelihood that, for a given chemical series, the in vitro kinetic data is predictive of in vivo clearance and is therefore appropriate to guide optimisation of compound metabolic stability.

  • 13.
    Svennebring, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The usefulness of Oie-Tozer's model in deriving pharmacokinetic changes in response to changes in the concentration of drug-binding plasma protein2016In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 46, no 7, p. 659-663Article, review/survey (Refereed)
    Abstract [en]

    1. Oie-Tozer's model can be used to derive changes in the distribution of drugs in relation to changes in the concentration of drug binding plasma proteins.2. Concerns have been raised that the model is invalid for this purpose because it does not account for active drug transport, pH differences between fluids and extracellular tissue binding.3. Here, it is demonstrated that these imperfections do not affect the outcome of the calculation.

  • 14.
    Svennebring, Andreas Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Investigation of the prerequisites for the optimization of specific plasma protein binding as a strategy for the reduction of first-pass hepatic metabolism2015In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 45, no 4, p. 286-301Article in journal (Refereed)
    Abstract [en]

    1. It is hypothesized that the deliberate structural tailoring of compounds designed for drug use to increase the specific plasma protein binding can be used to reduce first-pass hepatic metabolism. To test the feasibility of this hypothesis, a dataset of drugs with plasma protein binding of 90% or above divided into three classes including 50 acids, 44 bases and 69 neutrals was analyzed. 2. Among the drugs with >= 99% plasma protein binding, the fraction of the total dose existing in free form in vivo (free dose fraction) decreased in the following order: acids (0.55%) > neutrals (0.16%) > bases (0.08%). The order was different for the fraction of the total dose that existed in plasma protein bound form (plasma protein bound dose fraction): acids (58%) > neutrals (17%) = bases (18%). 3. The free fraction was poorly correlated with the partition coefficient (Log P). The lower aqueous solubility associated with high plasma protein binding was explained by differences in Log P and not by the plasma protein binding per se. The logarithm of the extrarenal clearance was correlated with Log P. For acids and bases, extrarenal clearance was also correlated with f(u). For neutrals, plasma protein binding had no protective effect.

  • 15.
    Svennebring, Andreas Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The impact of the concentration of drug binding plasma proteins on drug distribution according to Øie-Tozer's model2016In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 46, no 4, p. 307-314Article in journal (Refereed)
    Abstract [en]

    New equations have been developed from an updated version of Oie-Tozer's model expressing how the free concentration and volume of distribution change in relation to changes in the concentration of drug binding plasma proteins. This updated model accommodates more than one drug binding plasma protein to contribute to the plasma protein binding. Demonstrations of the model show that variability in the concentration of one plasma protein has considerably less impact on the free drug concentration and volume of distribution if other plasma proteins contribute to binding, than if they don't.

  • 16.
    Thörn, Helena Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yasin, Mohammed
    AstraZeneca R&D Alderley Park, Macclesfield, UK.
    Dickinson, Paul Alfred
    AstraZeneca R&D Alderley Park, Macclesfield, UK.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery2012In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 42, no 9, p. 917-928Article in journal (Refereed)
    Abstract [en]

    1. In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4'-beta-glucuronide (R-4-G).

    2. Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E G) during first-pass to more than 70% and a high concentration (AUC(0-6 h) ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E-H) of raloxifene was similar to 50% and as in humans the bioavailability become low (similar to 7%) in pigs. Interestingly the E-H of raloxifene and R-4-G was time-dependent after i.j. administration.

    3. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.

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