Drug Metabolism and Drug-Drug Interaction

A robust drug design process involves lead identification and optimization.  Two vital aspects that will be investigated are drug metabolism and drug-drug interaction (DDI). 

Drug metabolism refers to the biotransformation (enzymatic conversion) of a drug in the body so that it can be eliminated more easily. The main goal of this conversion process is to make a lipophilic molecule more hydrophilic (water-soluble) so it can be eliminated. The majority of metabolic processes that involve drugs occur in the liver, as the enzymes that facilitate the reactions are concentrated there.

Drug-drug interaction is a change in a drug’s effect on the body when the drug is taken together with a second drug. A drug-drug interaction can delay, decrease, or enhance absorption of either drug. 

Evaluating the DDI potential of an investigational new drug involves: 

• identifying the principal routes of the drug’s elimination
• estimating the contribution of enzymes and transporters to the drug’s disposition
• characterizing the effect of the drug on enzymes and transporters. 

Standard in vitro DDI studies can predict a compound’s likelihood to cause drug-drug interactions via up- or down-regulation of drug-metabolizing enzymes or drug transporters or their activities.

The most common application of plated hepatocytes for in vitro drug metabolism and pharmacokinetics (DMPK) studies is to determine the potential of drug-drug interactions via induction of the gene expression of various CYP450 enzymes. The amount and activity of these enzymes are known to increase when cells are exposed to certain chemical substances. However, an increase in the activity of a particular P450 enzyme might also affect a different drug in a patient's regime, leading to a drug-drug interaction (DDI) that could impact the efficacy and safety of more than one drug. Regulatory agencies require an analysis of the DDI potential in hepatocytes for CYP3A4, CYP1A2, and CYP2B6, which indicates whether a clinical DDI study is required. Our Cryopreserved Human Hepatocytes, Interaction qualified, (cat # HUCPI) are pre-characterized to exhibit enzyme induction levels recommended by the FDA for evaluation of DDI.

A second major application of plated hepatocytes is the determination of the inhibition of the transporter-mediated efflux of a substance by a particular drug. Our Interaction Qualified Hepatocytes (cat # HUCPI) are therefore also qualified for transporter function.  By characterizing for both enzyme induction and transporter function, we enable use of the same donor hepatocyte batch for different types of DDI studies.
 
Finally, the pharmaceutical discovery of drugs that are more slowly metabolized has become increasingly desirable. Slower drug metabolism translates into longer-lasting efficacious levels of a drug, so a patient can take the drug less frequently, which can increase compliance and decrease production costs. However, suspension hepatocytes are not viable or metabolically active long enough to allow the accurate measurement of the basic metabolic properties of such drugs. Since plated hepatocytes maintain their metabolic activity much longer than cells in suspension, researchers use them for assays that have a duration of four hours or longer. We qualify and report basal metabolism and clearance rates for several P450 enzymes in both of our plateable hepatocyte products, cat # HUCPG and cat # HUCPI.