MDR1 variants and methods for their use
View Patent ↗This invention provides the identification of a truncation polymorphism of the mdr1 gene that is linked to ivermectin sensitivity in subjects, such as collies. Also provided are methods for detecting drug transport sensitivity in a subject, and animal models and in vitro cell systems using cells from animals having an mdr1 truncation.
1. A method of screening for whether a compound has a biological effect in a canine cell having a truncated P-gp protein, comprising:
contacting a first canine cell with the compound, wherein the first canine cell has a truncation mutation in a mdr1 gene at residues 294-297 of SEQ ID NO: 1, which mutation results in the canine cell having a truncated P-gp protein, to produce a contacted canine cell; and
comparing a characteristic of the contacted canine cell with
a) the same characteristic of the first canine cell prior to contact with the compound,
b) the same characteristic of a similar canine cell not contacted with the compound, or
c) the same characteristic of a second canine cell contacted with the compound, wherein the second canine cell does not have a truncation mutation in its mdr1 gene;
wherein a difference in the characteristic indicates the compound has a biological effect in the canine cell having the truncated P-gp protein.
2. The method of claim 1 , wherein contacting the canine cells with the compound occurs in vivo.
3. The method of claim 1 , wherein the canine cell is a gastrointestinal tissue cell, a renal tissue cell, a brain capillary endothelial cell, a liver tissue cell, a placental cell, bronchiolar epithelial cell, or an adrenal cortical cell.
4. The method of claim 1 , wherein the characteristic of the cell being compared is genetic, physiological, chemical, or morphological.
5. The method of claim 1 , wherein the biological effect results from a defect in efflux of the compound from the contacted canine cell.
6. The method of claim 1 , wherein the first canine cell is a neoplastic canine cell.
7. The method of claim 1 , wherein the compound is a neurokinin receptor antagonist, anti-emetic agent, beta-adrenergic receptor antagonist, antiinfective agent, antiepileptic agent, antineoplastic agent, analgesic agent, anti-psychotic agent, anti-parasitic agent or anti-depressive agent.
8. The method of claim 1 , wherein the compound is an antiviral agent.
9. The method of claim 1 , wherein the canine cell is a dog cell.
10. The method of claim 9 , wherein the dog cell is a Collie cell.
11. The method of claim 1 , wherein the first canine cell is contacted in vitro.
12. The method of claim 2 , wherein contacting the first canine cell in vivo comprises administering the compound to a dog.