As drug development costs continue to escalate, determining toxicity and possible interactions with foods, herbal supplements, and other drugs as early as possible is crucial.
Drug response is variable owing to individual differences in the expression of drug-metabolizing enzymes as well as transporters at sites of absorption, elimination, and/or tissue distribution. This variability can result in unpredictable exposure and tissue distribution of drugs, which may be manifest as adverse effects or therapeutic failure.
Kuo-Chi Cheng, Ph.D., a fellow at Schering (www.schering.com), notes that this has always been a chief area of concern. “Historically, enzyme induction was a major issue, and the only way to unearth whether this was happening was by implementing an animal study around the compound of interest,” he says.
The majority of pharmacokinetic drug-drug interactions occur during drug metabolism in two ways. Either one drug (the perpetrator) may inhibit the metabolism of another drug (the victim), or a perpetrator drug may increase the metabolism of a victim drug. The latter is caused by induction of drug-metabolizing enzymes.
Induction of the major drug-metabolizing enzymes in humans is through activation of nuclear receptors. Assessing receptor activation by potential perpetrator compounds can predict whether there is a potential for drug-drug interactions.
Puracyp’s (www.puracyp.com) CSO, Judy Raucy, Ph.D., agrees. “Potential drug-drug interactions are a concern,” she says. “They can result from activation of nuclear receptors leading not only to alterations in the expression of drug-metabolizing enzymes and transporters, but changes in other biochemically important genes.”
She points out that PXR is a regulator of over 60 genes in the rat and more than 23 genes in humans. Therefore, activation of PXR can alter the disposition of foreign (xenobiotics) and endogenous (endobiotics) chemicals. “We’re not just talking about drug-drug interactions, we’re also considering the consequences of altering homeostasis. There isn’t any federal mandate to track that, but screening should be done as soon as drugs are synthesized in order to assess the activation of nuclear receptors,” Dr. Raucy notes.
Recently, new insights have been gained relating to the regulatory mechanisms governing the expression of drug-metabolizing enzymes and transporters by ligand-activated nuclear receptors. These receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules.
These receptors work in concert with other proteins to regulate the expression of specific genes, thereby controlling the metabolism, development, and homeostasis of the organism.
PXR, CAR, FXR, LXR, VDR, HNF4a, and AhR form a battery of nuclear receptors that regulate the expression of many important drug-metabolizing enzymes, transporters, lipid, bile acid, and cholesterol-metabolizing enzymes. For example, PXR and CAR are involved in controlling the metabolism and basolateral transport of bile acids; in addition these two receptors contribute to hepatic protection in cholestasis.
Recent evidence also suggests a role for PXR in cholesterol and steroid metabolism, maintaining mineral corticoid levels, and vitamin D regulation of bone homeostasis. Thus, increased activation of PXR or CAR can lead to alterations in concentrations of any of these key regulatory endobiotics. “The technology is becoming more mature,” says Dr. Cheng. “We are just beginning to understand how much induction translates in vivo. But we don’t yet understand the whole picture.”
Nuclear-receptor activation technology has been around for awhile; because of its ability to predict drug-drug interactions, it is a rapidly growing field. It is also useful for directing chemistry programs away from molecular structures that have liabilities that would activate important biotransformation genes, thus causing clinically significant drug-drug interactions.