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      The effect of chronic kidney disease on CYP2B expression and activity in male Wistar rats

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          Abstract

          Chronic kidney disease ( CKD) is characterized by progressive reduction in kidney function over time. CKD affects greater than 10% of the population and its incidence is on the rise due to the growing prevalence of its risk factors. Previous studies demonstrated CKD alters nonrenal clearance of drugs in addition to reducing renal clearance. We assessed the function and expression of hepatic CYP2B enzymes using a rat model of CKD. CKD was induced in Wistar rats by supplementing their chow with adenine and confirmed through the detection of elevated uremic toxins in plasma. Liver enzymes AST and ALT were unchanged by the adenine diet. Bupropion was used as a probe substrate for hepatic CYP2B function using rat liver microsomes. The resulting metabolite, hydroxy‐bupropion, and bupropion were quantified by ultra‐performance liquid chromatography coupled to time‐of‐flight mass spectrometry. Level of mRNA and protein were determined by RTPCR and Western blot, respectively. The results of our study demonstrate that CYP2B1 is downregulated in a rat model of CKD. CYP2B1 mRNA level was significantly decreased (88%, <  0.001) in CKD relative to control. Similarly, maximal enzymatic velocity ( V max) for CYP2B was decreased by 46% in CKD relative to control ( <  0.0001). Previous studies involving patients with CKD demonstrated altered bupropion pharmacokinetics compared to control. Hence, our results suggest that these alterations may be mediated by attenuated CYP2B hepatic metabolism. This finding may partially explain the alterations in pharmacokinetics and nonrenal drug clearance frequently observed in patients with CKD.

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          Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.

          Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of drug-metabolising enzymes. In this review the authors describe similarities and differences in this respect among the different species, including man. This may be helpful for drug researchers to choose the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. The authors focus on CYPs, which are the main enzymes involved in numerous oxidative reactions and often play a critical role in the metabolism and pharmacokinetics of xenobiotics. In addition, induction and inhibition of CYPs are compared among species. The authors conclude that CYP2E1 shows no large differences between species, and extrapolation between species appears to hold quite well. In contrast, the species-specific isoforms of CYP1A, -2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans.
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            Prevalence estimates of chronic kidney disease in Canada: results of a nationally representative survey.

            Chronic kidney disease is an important risk factor for death and cardiovascular-related morbidity, but estimates to date of its prevalence in Canada have generally been extrapolated from the prevalence of end-stage renal disease. We used direct measures of kidney function collected from a nationally representative survey population to estimate the prevalence of chronic kidney disease among Canadian adults. We examined data for 3689 adult participants of cycle 1 of the Canadian Health Measures Survey (2007-2009) for the presence of chronic kidney disease. We also calculated the age-standardized prevalence of cardiovascular risk factors by chronic kidney disease group. We cross-tabulated the estimated glomerular filtration rate (eGFR) with albuminuria status. The prevalence of chronic kidney disease during the period 2007-2009 was 12.5%, representing about 3 million Canadian adults. The estimated prevalence of stage 3-5 disease was 3.1% (0.73 million adults) and albuminuria 10.3% (2.4 million adults). The prevalence of diabetes, hypertension and hypertriglyceridemia were all significantly higher among adults with chronic kidney disease than among those without it. The prevalence of albuminuria was high, even among those whose eGFR was 90 mL/min per 1.73 m(2) or greater (10.1%) and those without diabetes or hypertension (9.3%). Awareness of kidney dysfunction among adults with stage 3-5 chronic kidney disease was low (12.0%). The prevalence of kidney dysfunction was substantial in the survey population, including individuals without hypertension or diabetes, conditions most likely to prompt screening for kidney dysfunction. These findings highlight the potential for missed opportunities for early intervention and secondary prevention of chronic kidney disease.
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              Comparison of the Complexity of Patients Seen by Different Medical Subspecialists in a Universal Health Care System

              Key Points Question Are there differences in the complexity of patients seen by different types of physicians? Findings In this population-based cohort study of 2.5 million Canadian adults, there were substantial differences in markers of complexity for patients seen by different types of physicians, including medical subspecialists. Patients seen by nephrologists, infectious disease specialists, and neurologists were consistently more complex, whereas patients seen by allergists, dermatologists, and family physicians consistently tended to be less complex. Meaning Substantial between-specialty differences were found in 9 different markers of patient complexity. The relative rank of the different specialties studied is less important than the finding that there are wide variations in complexity between specialties, which has implications for medical education and health policy.
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                Author and article information

                Contributors
                Brad.Urquhart@schulich.uwo.ca
                Journal
                Pharmacol Res Perspect
                Pharmacol Res Perspect
                10.1002/(ISSN)2052-1707
                PRP2
                Pharmacology Research & Perspectives
                John Wiley and Sons Inc. (Hoboken )
                2052-1707
                26 April 2019
                June 2019
                : 7
                : 3 ( doiID: 10.1002/prp2.2019.7.issue-3 )
                : e00475
                Affiliations
                [ 1 ] Department of Physiology and Pharmacology Schulich School of Medicine and Dentistry London Ontario Canada
                [ 2 ] Lawson Health Research Institute London Ontario Canada
                [ 3 ] Department of Medicine Division of Nephrology Schulich School of Medicine and Dentistry London Ontario Canada
                Author notes
                [*] [* ] Correspondence

                Bradley L. Urquhart, 1151 Richmond Street, Medical Sciences Building Room 216, London, Ontario N6A 5C1, Canada.

                Email: Brad.Urquhart@ 123456schulich.uwo.ca

                Author information
                https://orcid.org/0000-0001-9958-8964
                https://orcid.org/0000-0001-8324-1472
                Article
                PRP2475
                10.1002/prp2.475
                6484215
                31049204
                3f950fa4-1152-4ff0-ab96-214794a72920
                © 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 March 2019
                : 02 April 2019
                Page count
                Figures: 6, Tables: 1, Pages: 8, Words: 5609
                Funding
                Funded by: Natural Sciences and Engineering Research Council of Canada
                Funded by: Canada Foundation for Innovation
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                prp2475
                June 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:26.04.2019

                chronic kidney disease,cytochrome p450,hepatic drug metabolism,nonrenal clearance

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