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Microsomal and Cytosolic Scaling Factors in Dog and Human Kidney Cortex and Application for In Vitro-In Vivo Extrapolation of Renal Metabolic Clearance.

ABSTRACT: In vitro-in vivo extrapolation of drug metabolism data obtained in enriched preparations of subcellular fractions rely on robust estimates of physiologically relevant scaling factors for the prediction of clearance in vivo. The purpose of the current study was to measure the microsomal and cytosolic protein per gram of kidney (MPPGK and CPPGK) in dog and human kidney cortex using appropriate protein recovery marker and evaluate functional activity of human cortex microsomes. Cytochrome P450 (CYP) content and glucose-6-phosphatase (G6Pase) activity were used as microsomal protein markers, whereas glutathione-S-transferase activity was a cytosolic marker. Functional activity of human microsomal samples was assessed by measuring mycophenolic acid glucuronidation. MPPGK was 33.9 and 44.0 mg/g in dog kidney cortex, and 41.1 and 63.6 mg/g in dog liver (n = 17), using P450 content and G6Pase activity, respectively. No trends were noted between kidney, liver, and intestinal scalars from the same animals. Species differences were evident, as human MPPGK and CPPGK were 26.2 and 53.3 mg/g in kidney cortex (n = 38), respectively. MPPGK was 2-fold greater than the commonly used in vitro-in vivo extrapolation scalar; this difference was attributed mainly to tissue source (mixed kidney regions versus cortex). Robust human MPPGK and CPPGK scalars were measured for the first time. The work emphasized the importance of regional differences (cortex versus whole kidney-specific MPPGK, tissue weight, and blood flow) and a need to account for these to improve assessment of renal metabolic clearance and its extrapolation to in vivo.

SUBMITTER: Scotcher D

PROVIDER: S-EPMC5399648 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Microsomal and Cytosolic Scaling Factors in Dog and Human Kidney Cortex and Application for In Vitro-In Vivo Extrapolation of Renal Metabolic Clearance.

Scotcher Daniel D Billington Sarah S Brown Jay J Jones Christopher R CR Brown Colin D A CDA Rostami-Hodjegan Amin A Galetin Aleksandra A

Drug metabolism and disposition: the biological fate of chemicals 20170307 5

In vitro-in vivo extrapolation of drug metabolism data obtained in enriched preparations of subcellular fractions rely on robust estimates of physiologically relevant scaling factors for the prediction of clearance in vivo. The purpose of the current study was to measure the microsomal and cytosolic protein per gram of kidney (MPPGK and CPPGK) in dog and human kidney cortex using appropriate protein recovery marker and evaluate functional activity of human cortex microsomes. Cytochrome P450 (CYP ...[more]

PMID: 28270564

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Project description:BACKGROUND:Renal disease is considered the main cause of natural mortality in dogs with canine leishmaniosis. The pathological mechanisms associated with kidney injury in canine leishmaniosis include immune complex glomerulonephritis, tubulointerstitial nephritis and occasionally renal amyloidosis. Proteinuria is a frequent finding in canine leishmaniosis and its quantification by the urine protein-creatinine ratio (UPC) is an important parameter in the staging of canine lesihmaniosis as presented by the LeishVet group. RESULTS:A 4.5 year-old spayed female Belgian Malinois dog was presented to the Hebrew University Veterinary Teaching hospital with epistaxis and rhinitis and diagnosed also with proteinuria and acute kidney injury (AKI IRIS grade V) associated with canine leishmaniosis that developed to LeishVet stage III with chronic kidney disease (CKD) after stabilization. Clinicopathologic abnormalities included azotemia with a peak creatinine concentration of 7.76 mg/dl (reference interval, 0.3-1.2 ng/dl), hypoalbuminemia (1.76 g/dl, reference interval 3-4.4 g/dl), hyperglobulinemia (4.54 g/dl, reference interval 1.8-3.9 g/dl) and proteinuria (urine protein/creatinine ratio 15.6, normal < 0.2). Serology by the enzyme-linked immunosorbent assay (ELISA) for Leishmania infantum was positive with high antibody levels. The dog was hospitalized and treated with intermittent hemodialysis, feeding through an esophageal feeding tube, medical treatment for protein losing nephropathy and antileishmanial treatment with allopurinol. Kidney function gradually improved and the dog's creatinine levels and proteinuria decreased until complete normalization two years after the acute insult. However, rhinitis and sneezing persisted and although the anti-leishmanial antibodies decreased over time, the dog remains constantly seropositive. CONCLUSIONS:To our knowledge, this is the first report of hemodialysis management of AKI associated with canine leishmaniosis. Hemodialysis was imperative in stabilizing the dog's renal disease and controlling its azotemia. It demostrates that hemodialysis can be beneficial in the management of acute deterioration of kidney disease in canine leishmaniosis.

Dataset Information

Microsomal and Cytosolic Scaling Factors in Dog and Human Kidney Cortex and Application for In Vitro-In Vivo Extrapolation of Renal Metabolic Clearance.

Publications

Microsomal and Cytosolic Scaling Factors in Dog and Human Kidney Cortex and Application for In Vitro-In Vivo Extrapolation of Renal Metabolic Clearance.

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