Identifying and characterizing the effect of the enzymes responsible for the metabolism of a drug candidate is essential for pre-clinical programs. Evaluation of the potential for metabolite toxicity, drug-drug interactions (DDI) and pharmacokinetics can be done in a high throughput manner using edited reporter and knockout cell lines. The predominant Phase I drug metabolism ensymes (the CYPs) are traditionally studied by using specific chemical inhibitors. Now, however gene editing technology allows for the full knockout of all or individual CYPs leading to cleaner and more effective toxicity and ADME studies. UDP glucuronosyltransferases (UGT) are phase II metabolism enzymes responsible for conjugation reactions and biotransformation for drug excretion. Validated assays and specific inhibitors of UDP glucuronosyltransferases (UGT) enzymes have not been identified. In addition UGTs have an abundance of isoforms in drug eliminating organs, making determining of the contribution of each for elimination difficult. Gene editing technology can edit different gene isoforms specifically allowing researchers to identify which UGT is responsible for drug transport.
In addition to drug metabolism genes, drug transporters have pharmacological implications due to role in absorption, distribution, metabolism and elimination (ADME). Two transporter super families called solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters1 make up what is known as the ‘multispecific drug transporters’. ABC transporters function as efflux transporters by employing ATP hydrolysis, whereas SLC drug transporters are involved in uptake of small molecules and do not utilize ATP hydrolysis. According to the FDA guidance on Drug-Drug Interactions, all investigational drugs should be evaluated in vitro to determine whether they are a potential substrate for ABC transporters ABCB1 (also known as P-glycoprotein (PGP) or MDR1) and ABCG2 (also known as BCRP).Efforts are underway at Hera BioLabs to generate panels of specifically engineered cell lines for high throughput toxicity and metabolism/induction studies of drug transporters and metabolism activity.