Measuring Altered Disposition of Xenobiotics in Experimental Models of Liver Disease

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Abstract
Table of Contents
Materials
Figures
Literature Cited

Abstract

Understanding the metabolic pathway and excretion mechanisms governing the disposition of a compound is essential to the safe use of pharmaceutical agents. Because the liver is the primary organ responsible for the metabolism and elimination of xenobiotics, chronic liver disease can have a significant effect on the disposition of many xenobiotics due to changes in the expression or function of drug metabolizing enzymes and transporters. Liver disease can result in increased retention of a xenobiotic within the body, causing greater exposure of the individual to a potentially harmful compound, which may lead to toxicity. On the other hand, liver disease may also up?regulate the elimination processes of a xenobiotic, accelerating its removal from the body. With regard to a pharmaceutical agent, enhanced elimination may result in a decreased pharmacologic effect. Such alterations may necessitate dosage adjustments to achieve the desired therapeutic outcome. Curr. Protoc. Toxicol. 52:23.1.1?23.1.17. © 2012 by John Wiley & Sons, Inc.

Keywords: nonalcoholic fatty liver disease; drug disposition; nonalcoholic steatohepatitis; steatosis

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Introduction
Basic Protocol 1: Measurement of Xenobiotic Disposition in Rat Plasma and Bile Through Femoral Artery and Vein Cannulations and Common Bile Duct Cannulation
Alternate Protocol 1: Measurement of Xenobiotic Disposition in Mouse Plasma Through Carotid Artery and Jugular Vein Cannulations
Commentary
Literature Cited
Figures

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Materials

Basic Protocol 1: Measurement of Xenobiotic Disposition in Rat Plasma and Bile Through Femoral Artery and Vein Cannulations and Common Bile Duct Cannulation

Materials

Sprague‐Dawley rats (1.5 to 2 months old or 200 to 250 g)
Methionine‐ and choline‐deficient (MCD) diet (models NASH): Dyets, diet no. 518810, Choline Deficient and Iron Supplemented L‐Amino Acid Defined Diet without L‐Methionine
Control diet (serves as control to MCD diet): Dyets, diet no. 518754, Choline Sufficient and Iron Supplemented L‐Amino Acid Defined Diet
High fat (HF) diet (models simple steatosis): Dyets, diet no. 112280, High Cholesterol, 18% Butter Diet
Isocaloric diet (serves as control to HF diet): Dyets, diet no. 180820, Custom Low Fat Control Diet Isocaloric to diet no. 112280
Heparin: 100 USP U/ml (Hospira)
Heparinized saline: 10:1 mixture of saline and heparin (will need approximately 100 ml)
Urethane
Normal saline (NaCl): 0.9% (w/v), sterile‐filtered (will need approximately 250 ml)
10% povidone iodine prep solution
Lubricant for rectal probe (a water‐based lubricant such as KY Jelly works well)
Ice
Test compound

PE50 polyethylene tubing: 0.965 mm × 0.58 mm
23‐G needles for insertion in PE50 tubing for femoral cannula
1‐ml syringes (will need a minimum of one for each plasma time point collection)
3‐ml syringes for femoral vein cannula
PE10 polyethylene tubing: 0.6 mm × 0.28 mm
Silk suture: braided silk size 4/0, 0.17‐mm diameter (e.g., Fine Science Tools, cat. no. FST18020‐40)
Small animal electric clippers with size 40 ceramic edge 0.25‐mm blade
Small gauze sponges: 8 ply, 2 × 2 in.
Rodent temperature monitor and heat pad (e.g., Physitemp Instruments, cat. no. TCAT‐2V) with rectal probe (e.g., RET2 rectal probe for rats, Physitemp Instruments)
Tape
Small scissors: straight, sharp/blunt edges, 10‐cm length (e.g., Fine Science Tools, cat. no. FST14028‐10)
2 Graefe forceps with slight curve: serrated 0.8‐mm tip width, 10‐cm length, curved (e.g., Fine Science Tools, cat. no. FST11051‐10)
Kelly hemostats: serrated, 1.5‐mm tip width, curved, 14‐cm length (e.g., Fine Science Tool, cat. no. FST13019‐14)
Halsted‐Mosquito hemostats: serrated, 1.1‐mm tip width, curved, 12.5‐cm length (e.g., Fine Science Tools, cat. no. FST13009‐12)
Vannas‐Tübingen spring scissors: straight, 8.5‐cm, 5‐mm cutting edge, 0.1‐mm tip diameter (e.g., Fine Science Tools, cat. no. FST15003‐08)
Vessel dilating forceps: angled 10°, 0.2‐mm tip diameter, 11‐cm length (e.g., Fine Science Tools, cat. no. FST00125‐11)
Microdissection microscope
Toothed forceps: slim, 1 × 2 teeth (e.g., Fine Science Tools, cat. no. FST11023‐12)
Large scissors: straight, sharp/blunt edges, 12‐cm length (e.g., Fine Science Tools, cat. no. FST14001‐12)
50‐ml conical tube
Cotton‐tipped applicators
1.7‐ml microcentrifuge tubes (will need a minimum of one for each bile time point collection, tubes must be weighed before initiation of experiments)
Large gauze sponges: 8 ply, 4 × 4 in.
0.65‐ml microcentrifuge tubes, preheparinized (will need a minimum of two for each plasma time point collection)

Additional reagents and equipment for euthanizing the animal (Donovan and Brown, )

Alternate Protocol 1: Measurement of Xenobiotic Disposition in Mouse Plasma Through Carotid Artery and Jugular Vein Cannulations

C57/Bl6 mice (5 to 8 weeks old, or 20 to 25 g)
Ketamine
Xylazine

30‐G needles for insertion in carotid and jugular cannulas
Wire for securing retractor hooks: nylon‐coated stainless steel bead‐stringing wire, 0.61 mm (this can be purchased at any craft supply store)
Small retractor hook: blunt, 1‐mm wide (e.g., Fine Science Tools, cat. no. FST18200‐09; these come in a pack of 25 and can be re‐used if cleaned well)
Large retractor hook: blunt, 2.5‐mm wide (e.g., Fine Science Tools, cat. no. FST18200‐10; these com in a pack of 25 and can be re‐used if cleaned well)
Tape
Rodent temperature monitor and heat pad (e.g., Physitemp Instruments, cat. no. TCAT‐2V) with rectal probe (e.g., RET3 rectal probe for mice, Physitemp Instruments)
2 Graefe forceps with slight curve: serrated 0.8‐mm tip width, 10‐cm length, curved (e.g., Fine Science Tools, cat. no. FST11051‐10)
Graefe forceps with sharp curve: serrated 0.8‐mm tip width, 10‐cm length (e.g., Fine Science Tools, cat. no. FST11052‐10)
Forceps for applying microserrefines: serrated, 1.3‐mm tip width, 13‐cm length, curved (e.g., Fine Science Tools, cat. no. FST11009‐13)
3 Microserrefines: 4‐mm jaw length, 0.75‐mm jaw width, 16‐mm total length, 125 g jaw pressure (e.g., Fine Science Tools, cat. no. FST18055‐06)

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Figures

Figure 23.1.1 Femoral artery and vein cannulation and common bile duct cannulation of the rat. (A ) Left to right: saphenous nerve (white), femoral artery (pale pink, not clearly visible in image), femoral vein (dark red). (B ) Dissection of the saphenous nerve from the femoral artery. (C ) Passing of silk suture beneath the femoral artery. (D ) Ligation of the femoral artery distal to the peritoneum and incision of the femoral artery. (E ) Insertion of the cannula into the femoral artery. (F ) Tying of the femoral artery to the cannula using a silk suture. (G ) Dissection of the common bile duct from surrounding connective tissue. The liver is visible in the background. (H ) Ligation of the common bile duct proximal to the small intestine and tying of the common bile duct to the cannula.

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Figure 23.1.2 Diagram of cannulation and clamping procedures for cannulation of the carotid artery and jugular vein of the mouse.

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Literature Cited

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