Medical knowledge is the accumulation of aggregated learning, research, and observations. Research can be systematic, but discoveries can be also be serendipitous. I was thinking about serendipity and pharmaceuticals when I heard that Canadian pharmacist/pharmacologist David Bailey had recently died. Bailey made an unexpected discovery about drug metabolism and how food can profoundly affect the delivery of drugs into the body.
In the early 1990s I was completing a hospital residency program in London, Ontario. My residency supervisor told me about a surprising finding made by a PhD researcher who had been working with the pharmacy department. David Bailey was trying to determine if the absorption of a new antihypertensive medication, felodipine, was affected by alcohol. This was a double-blind test, so Bailey needed to mask the alcohol. He tried different liquids, but ultimately found grapefruit juice was the most successful beverage. The results were surprising. He found that felodipine levels dramatically exceeded predicted levels, which was hypothesized to have potentially been caused by an interaction between the felodipine and the grapefruit juice – a drug-food interaction which had not been previously identified.
Bailey’s next experiment was on himself. He took a dose of felodipine and drew blood levels. The next day he took the same dose, with grapefruit juice. He could soon feel the effects of rapidly lower blood pressure, and the blood levels of felodipine confirmed that something odd was happening. A subsequent small clinical trial (now with almost 800 citations) showed that this effect was substantial, reproducible, and appeared to be limited to grapefruit juice (orange juice had no similar effect). Until this point, no serious interactions between drugs and food had been shown.
The grapefruit-drug interaction that had been discovered was the pivot for Bailey’s entire research career from that point onwards. Bailey had grown up as an exceptional track and field athlete and was the first Canadian to run a sub-4-minute mile. As a pharmacist and then PhD researcher, he didn’t plan to spend his career exploring drug-food interactions. But after this discovery, he turned his research lens on this phenomenon. His team in London went on to study this phenomenon extensively.
How does grapefruit juice affect drug metabolism?
The body has a number of mechanisms to deal with unwanted chemicals that might be ingested. Drug metabolism is the conversion of a drug to an inactive form that can be excreted, usually in the urine. The most common pathway for drug metabolism is what’s called “cytochrome P450“. One enzyme, called cytochrome P450 3A4 inactivates many drugs we consume. This enzyme is found in cells that line the small intestine and colon, as well as the liver. This means that for drugs that we take orally, a substantial percentage of the dose taken may be eliminated in the intestines and then the liver. In the case of felodipine, the drug Bailey had first studied, the bioavailability (amount available to the body to have a drug-like effect) is only 15% of the dose actually consumed. Because it has low bioavailability, anything that affects the action of the 3A4 enzyme may change the amount of felodipine that reaches the bloodstream.
Furanocoumarins are compounds produced by grapefruits (and limes, Seville oranges, and pomelos) possibly as a predator defense. When ingested, they can permanently inhibit CYP3A4 by binding to the enzyme itself, inactivating it. Once inactivated, the enzyme cannot metabolize ingested drugs, leading to greater levels of drug in the bloodstream when the drug is taken orally. The body needs to replace the enzyme in order for activity to be restored.
Grapefruit eater/drinker? Check your medications!
Several dozen drugs have subsequently been shown to be potentially affected by grapefruit. Characteristics include oral dosage form, low natural bioavailability, and metabolism by the 3A4 enzyme. When grapefruit juice is taken with these medications, it can be the equivalent of taking 20x the dose. You can find lists online – or just ask your pharmacist if you’re a grapefruit eater/drinker and you take prescription medicines.
David Bailey died last month at age 77. If you ever receive a prescription with a sticker cautioning against taking grapefruit, give thanks to Bailey for his accidental discovery 30 years ago.