Publications by authors named "Alexandra Peric"

4 Publications

  • Page 1 of 1

Correlation of Body Weight and Composition With Hepatic Activities of Cytochrome P450 Enzymes.

J Pharm Sci 2021 01 19;110(1):432-437. Epub 2020 Oct 19.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway. Electronic address:

Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CL) values for CYP3A correlated negatively with body weight (r = -0.43, p < 0.01), waist circumference (r = -0.47, p < 0.01), hip circumference (r = -0.51, p < 0.01), fat percent (r = -0.41, p < 0.05), fat mass (r = -0.48, p < 0.01) and BMI (r = -0.46, p < 0.01). Linear regression analysis showed that CL values for CYP3A decreased with 5% with each 10% increase in body weight (r = 0.12, β = -0.558, p < 0.05). There were no correlations between body weight measures and CL values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.
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http://dx.doi.org/10.1016/j.xphs.2020.10.027DOI Listing
January 2021

A Comparative Analysis of Cytochrome P450 Activities in Paired Liver and Small Intestinal Samples from Patients with Obesity.

Drug Metab Dispos 2020 01 4;48(1):8-17. Epub 2019 Nov 4.

Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway (V.K., I.R., A.Å., H.C.); Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway (V.K., A.Å.); Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (A.P., C.W., S.A., T.B.A.); Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway (M.K.K.); Department of Health Sciences, OsloMet-Oslo Metropolitan University, Oslo, Norway (M.K.K.); Department of Pharmacy, Uppsala University, Uppsala, Sweden (C.W., P.A.); The Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A., J.H.); Department of Surgery, Vestfold Hospital Trust, Tønsberg, Norway (P.C.A.); Department of Endocrinology, Morbid Obesity and Preventive Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (J.H.); Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden (C.K.); Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (C.K.); and Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden (T.B.A.).

The liver and small intestine restrict oral bioavailability of drugs and constitute the main sites of pharmacokinetic drug-drug interactions. Hence, detailed data on hepatic and intestinal activities of drug metabolizing enzymes is important for modeling drug disposition and optimizing pharmacotherapy in different patient populations. The aim of this study was to determine the activities of seven cytochrome P450 (P450) enzymes in paired liver and small intestinal samples from patients with obesity. Biopsies were obtained from 20 patients who underwent Roux-en-Y gastric bypass surgery following a 3-week low-energy diet. Individual hepatic and intestinal microsomes were prepared and specific probe substrates in combined incubations were used for determination of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A activities. The activities of CYP2C8, CYP2C9, CYP2D6, and CYP3A were quantified in both human liver microsomes (HLM) and human intestinal microsomes (HIM), while the activities of CYP1A2, CYP2B6, and CYP2C19 were only quantifiable in HLM. Considerable interindividual variability was present in both HLM (9- to 23-fold) and HIM (5- to 55-fold). The median metabolic HLM/HIM ratios varied from 1.5 for CYP3A to 252 for CYP2C8. The activities of CYP2C9 in paired HLM and HIM were positively correlated ( = 0.74, < 0.001), while no interorgan correlations were found for activities of CYP2C8, CYP2D6, and CYP3A ( > 0.05). Small intestinal CYP3A activities were higher in females compared with males ( < 0.05). Hepatic CYP2B6 activity correlated negatively with body mass index ( = -0.72, < 0.001). These data may be useful for further in vitro-in vivo predictions of drug disposition in patients with obesity. SIGNIFICANCE STATEMENT: Hepatic and intestinal drug metabolism is the key determinant of oral drug bioavailability. In this study, paired liver and jejunum samples were obtained from 20 patients with obesity undergoing gastric bypass surgery following a 3-week low-energy diet. We determined the hepatic and small intestinal activities of clinically important P450 enzymes and provide detailed enzyme kinetic data relevant for predicting in vivo disposition of P450 substrates in this patient population.
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http://dx.doi.org/10.1124/dmd.119.087940DOI Listing
January 2020

Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis.

Sci Rep 2017 07 25;7(1):6352. Epub 2017 Jul 25.

Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca Gothenburg, Gothenburg, Sweden.

Knowledge about the region-specific absorption profiles from the gastrointestinal tract of orally administered drugs is a critical factor guiding dosage form selection in drug development. We have used a novel approach to study three well-characterized permeability and absorption marker drugs in the intestine. Propranolol and metoprolol (highly permeable compounds) and atenolol (low-moderate permeability compound) were orally co-administered to rats. The site of drug absorption was revealed by high spatial resolution matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and complemented by quantitative measurement of drug concentration in tissue homogenates. MALDI-MSI identified endogenous molecular markers that illustrated the villi structures and confirmed the different absorption sites assigned to histological landmarks for the three drugs. Propranolol and metoprolol showed a rapid absorption and shorter transit distance in contrast to atenolol, which was absorbed more slowly from more distal sites. This study provides novel insights into site specific absorption for each of the compounds along the crypt-villus axis, as well as confirming a proximal-distal absorption gradient along the intestine. The combined analytical approach allowed the quantification and spatial resolution of drug distribution in the intestine and provided experimental evidence for the suggested absorption behaviour of low and highly permeable compounds.
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http://dx.doi.org/10.1038/s41598-017-06583-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526999PMC
July 2017

In Vitro and In Vivo Modeling of Hydroxypropyl Methylcellulose (HPMC) Matrix Tablet Erosion Under Fasting and Postprandial Status.

Pharm Res 2017 04 2;34(4):847-859. Epub 2017 Feb 2.

Pharmacometrics Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 75124, Uppsala, Sweden.

Purpose: To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status.

Methods: A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent.

Results: Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (V) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of V depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm).

Conclusions: The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.
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http://dx.doi.org/10.1007/s11095-017-2113-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336534PMC
April 2017
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