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Poison Pills

The toolboxes of drug developers are already stocked with a host of simple cell-culture tests aimed at quickly predicting which would-be drugs will have toxic side effects. The problem with these tests is that they’re often too simple. A typical scenario: researchers squirt a solution containing an experimental medication into petri dishes where live cells harvested from a rat’s lungs float in a nutrient-rich broth. If the cells die, the researchers table the compound and try another; if the cells survive, they begin the lengthy and expensive process of testing the compound on mice, rats, and other animals. But the compound’s failure to kill the lung cells offers little insurance that it won’t make people sick.

When a person takes a drug, its active ingredient goes on a wild ride to get to the target cells: it might be absorbed by the gut, broken down by enzymes in the liver, hoarded for weeks by fat cells, screened out by a brain membrane, and whirled through the whole ordeal over and over again by the blood. When that happens, an otherwise harmless compound can accumulate in a particular organ until it reaches toxic levels. Or it can be transformed into a different compound altogether, which itself is toxic. Pfizer’s Reynolds estimates that, of drug candidates that end up proving unsafe, approximately 40 percent acquire their toxicity after being converted to other compounds in the body.

One reason that conventional cell-culture tests often mislead researchers is that they don’t present the complex brew of enzymes and other chemicals that a drug can encounter and react with in the various tissues of the body. And simple cell cultures don’t reveal how much of a drug actually gets to different types of cells, in what form, and for how long. Indeed, nearly half of the drugs that seem safe in cell-culture testing prove toxic in animal tests; and even more fail when they encounter the complex tissues and organs of humans. Researchers hope, however, that cell cultures that better simulate the conditions in the body will do a far better job at spotting toxic drugs, reducing the reliance on animal and human testing. “The holy grail of the industry is to be able to predict toxicity from a cell culture,” says Peter Lord, head of mechanistic toxicology in preclinical development at Johnson and Johnson Pharmaceutical Research and Development.

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Tagged: Biomedicine

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