Genetic diagnosis for qt prolongation related adverse drug reactions

A method of screening a pharmaceutical agent in vitro for its ability to induce prolonged cardiac repolarization in a cell comprising the steps of:

• (A) measuring IKr and IKs currents of the cell using a voltage clamp before superfusing the cell with a candidate agent or agents;
• (B) superfusing and incubating the cell with the candidate agent or agents;
• (C) measuring the IKr and IKs currents after superfusion and incubation of the cell with the candidate agent or agents using a voltage clamp;
• and
• (D) determining whether both the IKr or the IKs current is inhibited or abolished thereby indicating that the drug prolongs repolarization.

A method of screening two or more pharmaceutical agents in vitro for their ability to induce cardiac arrhythmias associated with QT interval elongation comprising the steps of:

• (A) measuring IKr and IKs currents of a cell using a voltage clamp before superfusing the cell with the two or more pharmaceutical agents;
• (B) superfusing and incubating the cell with the two or more pharmaceutical agents;
• (C) measuring the IKr and IKs currents after superfusing and incubation of the cell with the two or more pharmaceutical agents using a voltage clamp;
• (D) comparing the IKr and IKs currents of the combined pharmaceutical agents on the cell with the IKr and IKs currents of each of the pharmaceutical agents alone in the cell;
• and
• (E) determining whether the IKr and IKs currents are both inhibited such that beating of the cells is substantially inhibited.

A method of identifying a genetic polymorphism which can cause QT interval prolongation in a subject comprising the steps of:

• (A) inserting a nucleic acid or nucleic acids into a cell wherein the nucleic acid or nucleic acids encode at least two polymorphisms and/or mutations of at least two genes selected from the group of gene consisting of (1) LQT genes, (2) altered sensitivity genes and (3) increased exposure genes;
• (B) measuring IKs and IKr currents of the cell before administering a drug known to cause a change in IKs and/or IKr;
• (C) measuring IKs and IKr currents of the cell after superfusion of the cell with the drug;
• (D) comparing the IKs and IKr values of the cell expressing the polymorphisms and/or mutations to the IKs and IKr value of a cell expressing wild-type genes;
• and
• (E) determining if the presence of the mutations and/or polymorphisms leads to a greater inhibition or blockage of IKs and/or IKr.