Why is it that one person can have surgery and wake up, eat a full lunch and show no ill effects while others are sick for several days after receiving general anesthesia?
The fact is that we all process drugs differently, and these differences are a function of the genetic diversity between all of us. These differences stem from 1) different targets; 2) different liver enzyme activities; and 3) different levels of absorption, excretion and distribution.
A few examples might be illustrative. It is fairly well established that a particular type of blood pressure medicines called “ACE inhibitors” do not work terribly well in African-Americans (see Park IU, Taylor AL. Ann Fam Med. 2007 Sep-Oct;5(5):444-52). The reason for this is that the target of ACE inhibitors, the enzyme angiotensin converting enzyme, which is mercifully abbreviated ACE, works on a substrate that already exists at low concentrations in most African-American patients. Thus a target difference causes differential responses to particular blood pressure medicines.
As a second example, two liver enzymes that degrade drugs, Cyp2C19 and Cyp2D6 are encoded by genes that are subject to genetic variation. In 3-10% of whites, the Cyp2D6 enzyme does not completely function and the drugs processed by this enzyme, a blood pressure medicine called debrisoquine and a heart medicine called sparteine, show impaired degradation. Thus these patients are in danger of overdosing on these drugs at normal dosages, since they are degraded and excreted at such low rates. Other people, however, have a version of Cyp2D6 that is hyperactive. This variant is most commonly found in Ethiopians and Saudi Arabians that consequently, drugs degraded by this enzyme, such as tricyclic antidepressants (e.g., nortriptyline) must be dosed at two the three times the normal concentration. Also, some drugs are given as prodrugs, which are inactive until the liver activates them. In individuals with the overactive Cyp2D6 enzyme variant, a prodrug, such as codeine is overactivated and at normal doses, causes severe side effects (stomach pains). Thus a distinct enzyme difference causes different clinical outcomes with the same drugs (see JK Hicks, et al., Clin Pharmacol Ther. 2013 May;93(5):402-8).
So then, how do we test for drug safety and efficacy given these variations in drug metabolism?
Stem cell technology has the ability to improve drug testing in a multitude of ways. Drug safety can be tested with stem cells as can drug efficacy without feeding them to human volunteers.
Now scientists from the University of Edinburgh have shown that stem cell-based drug tests are almost ready for the prime time. David Hay from the Medical Research Centre for Regenerative Medicine at the University at the University of Edinburgh and his colleagues have generated cell in the laboratory that reach the gold standard required by the pharmaceutical industry to test drug safety.
In this study, the Hay laboratory made liver cells from H9 human embryonic stem cells and from 33D6 human induced pluripotent stem cells. Since is the liver is the main organ that biochemically processes drugs in our bodies (a phenomenon known as biotransformation), testing drug safety in cultured liver cells makes good sense.
Next, Hay and his colleagues found that these pluripotent-derived liver cells were equally effective in drug safety tests as frozen human liver tissue extracted from cadavers. Such livers are in short supply and the results researchers derive from them varies wildly according to the genetic make-up of the donor. Thus frozen liver tissue is not optimal for such drug testing protocols.
However, these drug-testing protocols that use stem cell-based protocols can provide reproducible drug safety results and can also be adapted for individuals with particular genetic compositions who process drugs differently from other people.
David Hay explained it this way: “Differing genetic information plays a key role in how patients’ livers process drugs. We are now able to efficiently produce human liver cells in the laboratory from different people model the functional differences in human genetics.”
Hay and others hope to generate liver cells that contain distinct DNA sequences that will reflect the genetic variations in metabolism found in the population. These cultured liver cells from human pluripotent stem cells can be used to identify differences in drug biotransformation.
These laboratory-generation liver cells could also be used to screen certain drugs that need close monitoring in order to optimize the efficacy of patient treatment, and the safety of these treatment regimes.
Hay and his colleagues are working with Edinburgh BioQuarter in order to form a spin-off company that will commercialize this research and its clinical ramifications.