Transgenic Non-Human Animals Comprising the Human Udp-Glucuronosyltransferase 1A (Ugt1a) Gene Locus and Methods of Using Them

17:

• A method of determining the pharmacokinetics, metabolism or toxicity of a compound comprising:
• (i) (a) providing the non-human transgenic animal of claim 1;
• (b) providing a test compound;
• (c) administering the test compound to the transgenic animal;
• and
• (d) determining the pharmacokinetics, metabolism or toxicity of the test compound in the non-human transgenic animal;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin derived from a microorganism;
• (iv) the method of (iii), wherein the environmental toxin is airborne, waterborne or a soil toxin;
• (v) the method of any of (i) to (iv), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (vi) the method of any of (i) to (v), wherein the non-human transgenic animal is pregnant or pseudopregnant;
• or
• (vii) the method of any of (i) to (vi), wherein the endogenous UGT1A gene locus of the non-human transgenic animal is partially or completed disabled (knocked out).

24:

• A method of determining if a compound induces or upregulates activity in a human UDP-glucuronosyltransferase 1A (UGT1A) gene locus comprising:
• (i) (a) providing the non-human transgenic animal of claim 1;
• (b) providing a test compound;
• (c) administering the test compound to the transgenic animal;
• and
• (d) measuring activity of the human UDP-glucuronosyltransferase 1A (UGT1A) gene locus in the non-human transgenic animal, cell, cell line, tissue or isolated organ, thereby determining if the test compound induced or upregulated activity in the non-human transgenic animal;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin derived from a microorganism;
• (iv) the method of (i), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (v) the method of any of (i) to (iv), wherein measuring activity of the human UDP-glucuronosyltransferase 1A (UGT1A) gene locus comprises measuring the chemical modification of the test compound;
• (vi) the method of any of (v), wherein the chemical modification of the test compound to a hydrophilic glucuronide is determined;
• or
• (vii) the method of any of (i) to (vi), wherein the non-human transgenic animal is pregnant or pseudopregnant.

31:

• A method of whether a compound is modified by the human UDP-glucuronosyltransferase 1A (UGT1A) gene locus pathway comprising:
• (i) (a) providing the non-human transgenic animal of claim 1;
• (b) providing a test compound;
• (c) administering the test compound to the transgenic animal;
• and
• (d) measuring the chemical modification of the test compound in the non-human transgenic animal;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin, derived from a microorganism;
• (iv) the method of (i), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (v) the method of any of (i) to (iv), wherein measuring activity of the human UDP-glucuronosyltransferase 1A (UGT1A) gene locus comprises measuring the chemical modification of the test compound;
• (vi) the method of any of (v), wherein the chemical modification of the test compound to a hydrophilic glucuronide is determined;
• or
• (vii) the method of any of (i) to (vi), wherein the non-human transgenic animal is pregnant or pseudopregnant.

37:

• A method of determining the pharmacokinetics, metabolism or toxicity of a compound comprising:
• (i) (a) providing the cell of claim 11;
• (b) providing a test compound;
• (c) administering the test compound to the cell;
• and (d) determining the pharmacokinetics, metabolism or toxicity of the test compound in the cell;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin derived from a microorganism;
• (iv) the method of (iii), wherein the environmental toxin is airborne, waterborne or a soil toxin;
• (v) the method of any of (i) to (iv), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (vi) the method of any of (i) to (v), wherein the endogenous UGT1A gene locus of the cell is partially or completed disabled (knocked out).

38:

• A method of determining the pharmacokinetics, metabolism or toxicity of a compound comprising:
• (i) (a) providing the tissue of claim 13;
• (b) providing a test compound;
• (c) administering the test compound to the tissue;
• and (d) determining the pharmacokinetics, metabolism or toxicity of the test compound in the tissue;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin derived from a microorganism;
• (iv) the method of (iii), wherein the environmental toxin is airborne, waterborne or a soil toxin;
• (v) the method of any of (i) to (iv), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (vi) the method of any of (i) to (v), wherein endogenous UGT1A gene locus of the tissue is partially or completed disabled (knocked out).

39:

• A method of determining the pharmacokinetics, metabolism or toxicity of a compound comprising:
• (i) (a) providing the isolated organ of claim 14;
• (b) providing a test compound;
• (c) administering the test compound to the isolated organ;
• and (d) determining the pharmacokinetics, metabolism or toxicity of the test compound in the isolated organ;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin derived from a microorganism;
• (iv) the method of (iii), wherein the environmental toxin is airborne, waterborne or a soil toxin;
• (v) the method of any of (i) to (iv), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (vi) the method of any of (i) to (v), wherein endogenous UGT1A gene locus of the isolated organ is partially or completed disabled (knocked out).

40:

• A method of determining if a compound induces or upregulates activity in a human UDP-glucuronosyltransferase 1A (UGT1A) gene locus comprising:
• (i) (a) providing the cell of claim 11;
• (b) providing a test compound;
• (c) administering the test compound to the cell;
• and (d) measuring activity of the human UDP-glucuronosyltransferase 1A (UGT1A) gene locus in the cell, thereby determining if the test compound induced or upregulated activity in the cell;
• (ii) the method of (i), wherein the test compound comprises a drug, a small molecule, a polymer, a toxin, a steroid, a heme metabolite, a cosmetic, a lotion, a food, a food or dietary supplement, an herbicide, a pesticide, a pollutant or a natural product;
• (iii) the method of (ii), wherein the toxin comprises an environmental toxin, a toxin derived from a natural product, a biological warfare agent or a toxin derived from a microorganism;
• (iv) the method of (i), wherein the test compound comprises a protein, a peptide, a nucleic acid, a carbohydrate, a polysaccharide, a fat, a steroid or a small molecule;
• (v) the method of any of (i) to (iv), wherein measuring activity of the human UDP-glucuronosyltransferase 1A (UGT1A) gene locus comprises measuring the chemical modification of the test compound;
• or
• (vi) the method of any of (v), wherein the chemical modification of the test compound to a hydrophilic glucuronide is determined.